angiotensinogen and Hypertension

Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LR

Topics: Angiotensin II; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Humans; Hypertension; Renin-Angiotensin System; RNA, Small Interfering

Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent

Topics: Acetylgalactosamine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Humans; Hypertension; Renin; Renin-Angiotensin System; RNA, Small Interfering

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

Topics: Angiotensinogen; Female; Humans; Hypertension; Kidney Diseases; Oligonucleotides, Antisense; Pregnancy; Renin; Renin-Angiotensin System; RNA, Small Interfering

The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen-the precursor substrate of the RAAS pathway-remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.

Topics: Angiotensinogen; Cardiovascular Diseases; Heart Failure; Humans; Hypertension; Oligonucleotides, Antisense; Peptide Hormones; Renin-Angiotensin System; RNA

Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene

Topics: Aldosterone; Angiotensin II; Angiotensinogen; Cardiovascular Diseases; CCAAT-Enhancer-Binding Proteins; Cytochrome P-450 CYP11B2; DNA Methylation; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Hypertension; Promoter Regions, Genetic; Transcription Factors

To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases.. Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease.. Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence.

Topics: Angiotensinogen; Animals; Humans; Hypertension; Oligonucleotides, Antisense; Renin-Angiotensin System; RNA, Small Interfering

Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine.. Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin.

Topics: Angiotensin II; Angiotensinogen; Animals; Humans; Hypertension; Kidney; Low Density Lipoprotein Receptor-Related Protein-2; Mice; Renin; Renin-Angiotensin System

Angiotensinogen (AGT) is the unique substrate of all angiotensin peptides. We review the recent preclinical research of AGT antisense oligonucleotides (ASOs), a rapidly evolving therapeutic approach. The scope of the research findings not only opens doors for potentially new therapeutics of hypertension and many other diseases, but also provides insights into understanding critical physiological and pathophysiological roles mediated by AGT.

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Evaluation, Preclinical; Genetic Therapy; Humans; Hypertension; Kidney; Liver; Molecular Targeted Therapy; Oligonucleotides, Antisense; Rats, Inbred SHR; Renin-Angiotensin System

Hypertension is one of the most important risk factors and a leading cause of death from cardiovascular and cerebrovascular diseases. Based on numerous previous studies, hypertension is thought to be caused by the complex mutual interactions of genetic factors and environmental factors, such as excessive salt intake and stress. However, its detailed mechanisms are not yet clearly understood. The renin-angiotensin system (RAS) is a key hormonal system in the pathogenesis of hypertension. New knowledge is still accruing on this cascade, even after more than 120 years since the discovery of renin. To clarify the molecular mechanisms of RAS in vivo, we created transgenic mice with chronic hypertension. These mice carry the human genes encoding renin, a hypertensive enzyme, and its substrate angiotensinogen. Hypotensive mice homozygous for a targeted disruption of the angiotensinogen gene were also created. This review presents our 47-year history of RAS research.

Topics: Angiotensinogen; Animals; Humans; Hypertension; Renin-Angiotensin System

Renin angiotensin system (RAS) is an endogenous hormone system involved in the control of blood pressure and fluid volume. Dysregulation of RAS has a pathological role in causing cardiovascular diseases through hypertension. Among several key components of RAS, angiotensin peptides, varying in amino acid length and biological function, have important roles in preventing or promoting hypertension, cardiovascular diseases, stroke, vascular remodeling etc. These peptides are generated by the metabolism of inactive angiotensinogen or its derived peptides by hydrolyzing action of certain enzymes. Angiotensin II, angiotensin (1-12), angiotensin A and angiotensin III bind primarily to angiotensin II type 1 receptor and cause vasoconstriction, accumulation of inflammatory markers to sub-endothelial region of blood vessels and activate smooth muscle cell proliferation. Moreover, when bound to angiotensin II type 2 receptor, angiotensin II works as cardio-protective peptide and halt pathological cell signals. Other peptides like angiotensin (1-9), angiotensin (1-7), alamandine and angiotensin IV also help in protecting from cardiovascular diseases by binding to their respective receptors.

Topics: Angiotensin I; Angiotensin II; Angiotensin III; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Humans; Hypertension; Oligopeptides; Peptide Fragments; Protective Factors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction; Vasoconstriction

Renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating renal hemodynamics and functions, as well as in the pathophysiology of hypertension and renal disease. In the kidney, angiotensin II (Ang II) production is controlled by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid with much higher concentrations than those existing in the circulation. Inappropriate activation of the intrarenal RAAS is an important contributor to the pathogenesis of hypertension and renal injury. It has been revealed that intrarenal Ang II levels are predominantly regulated by angiotensinogen and therefore, urinary angiotensinogen could be a biomarker for intrarenal Ang II generation. In addition, recent studies have demonstrated that aldosterone contributes to the progression of renal injury via direct actions on glomerular podocytes, mesangial cells, proximal tubular cells and tubulo-interstitial fibroblasts through the activation of locally expressed mineralocorticoid receptor. Thus, it now appears that intrarenal RAAS is independently regulated and its inappropriate activation contributes to the pathogenesis of the development of hypertension and renal disease. This short review article will focus on the independent regulation of the intrarenal RAAS with an emphasis on the specific role of angiotensinogen.

Topics: Angiotensin II; Angiotensinogen; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension; Kidney; Kidney Diseases; Renin; Renin-Angiotensin System

Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF).. Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Chymases; Heart Failure; Humans; Hypertension; Peptide Fragments; Receptors, Angiotensin; Renin-Angiotensin System

Many studies have suggested that polymorphisms of three key genes (ACE, AGT and CYP11B2) in the renin-angiotensin-aldosterone system (RAAS) play important roles in the development of blood pressure (BP) salt sensitivity, but they have revealed inconsistent results. Thus, we performed a meta-analysis to clarify the association. PubMed and Embase databases were searched for eligible published articles. Fixed- or random-effect models were used to pool odds ratios and 95% confidence intervals based on whether there was significant heterogeneity between studies. In total, seven studies [237 salt-sensitive (SS) cases and 251 salt-resistant (SR) controls] for ACE gene I/D polymorphism, three studies (130 SS cases and 221 SR controls) for AGT gene M235T polymorphism and three studies (113 SS cases and 218 SR controls) for CYP11B2 gene C344T polymorphism were included in this meta-analysis. The results showed that there was no significant association between polymorphisms of these three polymorphisms in the RAAS and BP salt sensitivity under three genetic models (all p > 0.05). The meta-analysis suggested that three polymorphisms (ACE gene I/D, AGT gene M235T, CYP11B2 gene C344T) in the RAAS have no significant effect on BP salt sensitivity.

Topics: Angiotensinogen; Blood Pressure; Blood Pressure Determination; Case-Control Studies; Cytochrome P-450 CYP11B2; Gene Expression; Humans; Hypertension; Models, Genetic; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Sodium Chloride, Dietary

The renin-angiotensin system is involved in hypertension and, thus, in cardiac and vascular injury. In general, angiotensin II is considered as the main mediator of this system but angiotensin IIderived peptides were also shown to exert effects in such diseases. Moreover, it became obvious that different cell and corresponding tissue types are characterized by their own renin-angiotensin system. This system is composed of various peptidic derivatives of the precursor angiotensinogen. Those angiotensinogen-derived peptides can be processed further by peptidases and can bind corresponding receptors. Various clinical trials were initiated considering inhibition of the renin-angiotensin system at different stages in cardiac injuries. Recently, a phase 3 trial using infused angiotensin II (LJPC-501) as treatment option in catecholamine-resistent hypotension was established (ClinicalTrials.gov identifier NCT02338843) although it might be that an influence of AngII-derived peptides is not considered. In general, more intense research on AngII-derived peptides should result in novel strategies and therapeutic options in treatment of cardiac and vascular injuries since these peptides exert actions by themselves, some may interfere with AngII-mediated effects, and some can bind different receptors as well. Consequently, they may also become new promising therapeutics in clinical settings in the future. This short review introduces all currently known angiotensins at once, their production and role related to cardiac and vascular injury, which immune cells show renin-angiotensin system components, and how immune cells containing such components might be involved in such diseases as well.

Topics: Angiotensin II; Angiotensinogen; Angiotensins; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Humans; Hypertension; Renin-Angiotensin System

It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na(+) reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT1 (AT1a) receptor- and/or megalin-mediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT1 (AT1a) receptors and Na(+)/H(+) exchanger 3, may provide a powerful feedforward mechanism for promoting Na(+) retention and the development of ANG II-induced hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Female; Humans; Hypertension; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Male; Prorenin Receptor; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin-Angiotensin System; Sodium; Sodium-Hydrogen Exchangers; Up-Regulation; Vacuolar Proton-Translocating ATPases

In angiotensin (Ang)-II-dependent hypertension, collecting duct renin synthesis and secretion are stimulated despite suppression of juxtaglomerular (JG) renin. This effect is mediated by Ang II type 1 (AT1) receptor independent of blood pressure. Although the regulation of JG renin is known, the mechanisms by which renin is regulated in the collecting duct are not completely understood. The presence of renin activity in the collecting duct may provide a pathway for intratubular Ang II formation since angiotensinogen substrate and angiotensin converting enzyme are present in the distal nephron. The recently named new member of the renin-angiotensin system (RAS), the (pro)renin receptor [(P)RR], is able to bind renin and the inactive prorenin, thus enhancing renin activity and fully activating prorenin. We have demonstrated that renin and (P)RR are augmented in renal tissues from rats infused with Ang II and during sodium depletion, suggesting a physiological role in intrarenal RAS activation. Importantly, (P)RR activation also causes activation of intracellular pathways associated with increased cyclooxygenase 2 expression and induction of profibrotic genes. In addition, renin and (P)RR are upregulated by Ang II in collecting duct cells. Although the mechanisms involved in their regulation are still under study, they seem to be dependent on the intrarenal RAS activation. The complexities of the mechanisms of stimulation also depend on cyclooxygenase 2 and sodium depletion. Our data suggest that renin and (P)RR can interact to increase intratubular Ang II formation and the activation of profibrotic genes in renal collecting duct cells. Both pathways may have a critical role in the development of hypertension and renal disease.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Humans; Hypertension; Kidney Diseases; Peptidyl-Dipeptidase A; Rats; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

Angiotensinogen (AGT) has a central role in maintaining blood pressure and fluid balance. DNA methylation is an epigenomic modification maintaining a steady pattern in somatic cells. Herein we summarize the link between AGT regulation and DNA methylation. DNA methylation negatively regulates AGT expression and dynamically changes in response to continuous AGT promoter stimulation. High-salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT enhancer-binding protein-binding sites, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue. Salt-dependent hypertension may be partially affected by increased adipose AGT expression. Because angiotensin II is a well-established aldosterone-releasing hormone, stimulation of adipose AGT by aldosterone creates a positive feedback loop. This effect is pathologically associated with obesity-related hypertension, although it would be physiologically favorable for humans to efficiently retain their body fluid. The clear difference in DNA demethylation patterns between aldosterone and cortisol indicates a difference in the respective target DNA-binding sites between mineralocorticoid and glucocorticoid receptors in the AGT promoter. Stimulation-induced interactions between transcription factors and target DNA-binding sites trigger DNA demethylation. Dynamic changes in DNA methylation occur in relaxed chromatin regions both where transcription factors actively interact and where transcription is initiated. In contrast to rapid histone modifications, DNA demethylation and remethylation will progress relatively slowly over days or years. A wide variety of stimuli in daily life will continue to slowly and dynamically change DNA methylation patterns throughout life. Wise choices of beneficial stimuli will improve health.

Topics: Angiotensinogen; DNA Methylation; Gene Expression Regulation; Gene-Environment Interaction; Humans; Hypertension; Obesity; Promoter Regions, Genetic

Experimental models of hypertension and patients with inappropriately increased renin formation due to a stenotic kidney, arteriosclerotic narrowing of the renal arterioles or a rare juxtaglomerular cell tumor have shown a progressive augmentation of the intrarenal/intratubular renin-angiotensin system (RAS). The increased intrarenal angiotensin II (Ang II) elicits renal vasoconstriction and enhanced tubular sodium reabsorption in proximal and distal nephron segments. The enhanced intrarenal Ang II levels are due to both increased Ang II type 1 (AT1) receptor mediated Ang II uptake and AT1 receptor dependent stimulation of renal angiotensinogen (AGT) mRNA and augmented AGT production. The increased AGT formation and secretion into the proximal tubular lumen leads to local formation of Ang II, which stimulates proximal transporters such as the sodium/hydrogen exchanger. Enhanced AGT production also leads to spillover of AGT into the distal nephron segments as reflected by AGT in the urine, which provides an index of intrarenal RAS activity. There is also increased Ang II concentration in distal nephron with stimulation of distal sodium transport. Increased urinary excretion of AGT has been demonstrated in patients with hypertension, type 1 and type 2 diabetes mellitus, and several types of chronic kidney diseases indicating an upregulation of intrarenal RAS activity.

Topics: Angiotensin II; Angiotensinogen; Animals; Biological Transport; Humans; Hypertension; Kidney Diseases; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Sodium; Vasoconstriction

Numerous studies have evaluated the association between the angiotensinogen (AGT) G-217A gene polymorphism and essential hypertension risk. However, the results have been inconsistent. We examined whether the AGT G-217A gene polymorphism confers essential hypertension risk by conducting a meta-analysis. We conducted a literature search of the Google Scholar, PubMed, and China National Knowledge Infrastructure databases for relevant studies that examined the G-217A polymorphism and risk of essential hypertension. Statistical analyses were carried out using Stata 12.0 to combine all relevant studies. Crude odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated to estimate the strength of this association. A total of 2017 patients with psoriasis and 1708 controls from 7 comparative studies were included in this meta-analysis. We found a significant association between the AGT G-217A gene polymorphism and the risk of essential hypertension (AA vs GG: OR = 2.52, 95%CI = 1.68-3.78; AA vs GA: OR = 2.26, 95%CI = 1.48-3.45; dominant model: OR = 0.38, 95%CI = 0.26-0.57; recessive model: OR = 1.20, 95%CI = 1.03-1.39). Further stratified analyses were conducted by ethnicity and sample size and produced similar results. No evidence of publication bias was found. This meta-analysis confirms that the AGT G-217A gene polymorphism is associated with essential hypertension susceptibility.

Topics: Angiotensinogen; Essential Hypertension; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Single Nucleotide; Risk Factors

The A-20C polymorphism in the angiotensinogen (AGT) gene has been associated with increased risk of essential hypertension in several studies; however, these studies gave inconsistent results. In this study, we performed a meta-analysis to assess the association between AGT A-20C polymorphism and essential hypertension. Published literature was retrieved from PubMed. Pooled odd's ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effect models. A total of 10 case-control studies containing 3653 cases and 3457 controls were enrolled to this meta-analysis. In a combined analysis, the results showed a significant association between the AGT A-20C polymorphism and risk of essential hypertension (AA vs CC: OR = 0.62, 95%CI = 0.46-0.84; recessive model: OR = 0.66, 95%CI = 0.49-0.88). In the subgroup analysis stratified by race, significant associations were found between the AGT A-20C polymorphism and essential hypertension risk in Asians (AA vs CC: OR = 0.59, 95%CI = 0.43-0.80; recessive model: OR = 0.63, 95%CI = 0.46-0.85). In conclusion, the results of this meta-analysis suggested that the AGT A-20C polymorphism was associated with risk of essential hypertension in Asians.

Topics: Angiotensinogen; Asian People; Essential Hypertension; Genetic Predisposition to Disease; Humans; Hypertension; Odds Ratio; Polymorphism, Single Nucleotide

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidneys and is marked by progressive cyst growth and decline in kidney function, resulting in end-stage renal disease (ESRD). Hypertension is thought to be a significant modifying factor in the progression of renal failure in ADPKD. A number of genetic variations involved in renin-angiotensin-aldosterone system (RAAS) pathway genes have clinical or physiological impacts on pathogenesis of hypertension-induced ESRD in ADPKD. Information on RAAS pathway gene polymorphisms and their association with ESRD and ADPKD, published till March 2013, was collected using MEDLINE search. The present review deals with RAAS gene polymorphisms focused on hypertension-induced ESRD in ADPKD in different populations. The results were inconclusive and limited by heterogeneity in the study designs and the population stratification. In lieu of applying next generation sequencing technologies to study complex diseases, it is also possible to apply the same to unravel the complexity of ESRD in ADPKD.

Topics: Angiotensinogen; Cytochrome P-450 CYP11B2; Humans; Hypertension; Kidney Failure, Chronic; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polycystic Kidney, Autosomal Dominant; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System

Circulating levels of the renin-angiotensin-aldosterone system (RAAS) components showed circadian oscillations in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Cardiac gene expression of the RAAS components also showed circadian variations in both SHR and WKY rats. Of interest, the amplitudes of these circadian fluctuations were different between SHR and WKY rats. Cardiac gene expression levels of the RAAS components were increased in SHR compared to WKY rats at many time points (especially during the active phase). The physiologic relevance of the differential circadian rhythms of circulating and cardiac gene expression levels of the RAAS components remains to be elucidated.

Topics: Angiotensinogen; Animals; Blood Pressure; Circadian Rhythm; Disease Models, Animal; Humans; Hypertension; Renin-Angiotensin System

Activated intrarenal renin-angiotensin system plays a cardinal role in the pathogenesis of hypertension and chronic kidney disease. Angiotensinogen is the only known substrate for renin, which is the rate-limiting enzyme of the renin-angiotensin system. Because the levels of angiotensinogen are close to the Michaelis-Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin-angiotensin system activity, and thus, upregulation of angiotensinogen leads to an increase in the angiotensin II levels and ultimately increases blood pressure. Recent studies using experimental animal models have documented the involvement of angiotensinogen in the intrarenal renin-angiotensin system activation and development of hypertension. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in experimental models of hypertension and chronic kidney disease, supporting the important roles of angiotensinogen in the development and the progression of hypertension and chronic kidney disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status in angiotensin II-infused rats. Also, a direct quantitative method has been developed recently to measure urinary angiotensinogen using human angiotensinogen enzyme-linked immunosorbent assay. These data prompted us to measure urinary angiotensinogen in patients with hypertension and chronic kidney disease, and investigate correlations with clinical parameters. This short article will focus on the role of the augmented intrarenal angiotensinogen in the pathophysiology of hypertension and chronic kidney disease. In addition, the potential of urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertension and chronic kidney disease will be also discussed.

Topics: Angiotensinogen; Animals; Biomarkers; Gene Expression Regulation; Humans; Hypertension; Rats; Renal Insufficiency, Chronic; Renin-Angiotensin System

Although the existence of a complete intrarenal renin-angiotensin system is now well established, its role in modulating tubule sodium transport and blood pressure is incompletely understood. Several recent studies have shed light on one component of the system, proximal tubule-derived angiotensinogen (AGT). This review discusses the synthesis, regulation and function of AGT in the proximal tubule.. Under normal sodium intake, AGT within the S1 and S2 segments of the proximal tubule may derive from the systemic circulation, whereas the S3 segment synthesizes AGT. Urinary AGT likely primarily reflects proximal tubule-derived AGT. Proximal tubule AGT synthesis is regulated by high Na intake, angiotensin-II and inflammatory cytokines. Transgenic expression of mouse AGT in the proximal tubule causes hypertension. Overexpression of rat AGT in the proximal tubule leads to hypertension, enhanced reactive oxygen species generation via NADPH oxidase, tubular apoptosis and tubulointerstitial fibrosis; these effects can be mitigated by catalase overexpression.. Proximal tubule-derived AGT has the potential to modulate blood pressure and sodium balance, and promote renal injury. Interactions with the systemic renin-angiotensin system may influence the role of proximal tubule-derived AGT in the kidney.

Topics: Angiotensinogen; Animals; Blood Pressure; Homeostasis; Humans; Hypertension; Kidney Tubules, Proximal; Sodium; Water

No consensus has been reached on the association between the angiotensinogen gene polymorphism T174M and hypertension risk in the Chinese population. We conducted a meta-analysis to systematically pursue their possible association. Case-control studies in the Chinese and English publications were identified by searching the MEDLINE, EMBASE, CBM, CNKI, Wanfang and VIP databases. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. After this, we selected 16 studies that met the inclusion criteria. In total, the selected studies contributed a study population containing 3828 hypertensive patients and 3251 normotensive controls. We found no statistical association between the T174M polymorphism and hypertension risk in all subjects, in a Han Chinese subgroup or in non-Han Chinese minorities. However, a statistically significant association was observed between the T174M polymorphism and a hypertensive group (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥95 mm Hg) in the dominant genetic model (MM+MT vs. TT: P=0.03, odds ratio=1.71, 95% confidence interval 1.07-2.74, P(heterogeneity)=0.27, I(2)=24%, fixed-effects model). No evidence of publication bias was observed. More studies, especially studies stratified for different stages of hypertension, should be performed in the future to fully examine this question. Studies investigating gene-gene interactions, gene-environment interactions, as well as their mutual interactions will also be important.

Topics: Alleles; Angiotensinogen; Blood Pressure; China; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Single Nucleotide

Although the angiotensinogen (AGT) gene has been implicated in the pathogenesis of essential hypertension, the results have been inconsistent. In this study, we performed a meta-analysis to assess the association of A-6G, A-20C and G-217A polymorphisms in the AGT gene with essential hypertension in the Chinese population.. Published literature from PubMed, Embase, China National Knowledge Infrastructure, China Biological Medicine and Wanfang Data was retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects models.. Sixteen studies (4223 cases and 3743 controls) for A-6G polymorphism, ten studies (3116 cases and 2678 controls) for A-20C polymorphism and five studies (1268 cases and 1081 controls) for G-217A polymorphism were identified. The results from the meta-analyses indicated significant association of all three polymorphism with the risk of essential hypertension in the Chinese population (A-6G polymorphism: GG vs AA: OR = 1.45, 95% CI 1.17-1.81; A-20C polymorphism: CC vs AA: OR = 1.52, 95% CI 1.10-2.08; G-217A polymorphism: AA vs GG: OR = 2.36, 95% CI 1.44-3.89).. Our study indicated that three polymorphisms (A-6G, A-20C and G-217A) in the AGT gene are associated with essential hypertension in the Chinese population.

Topics: Angiotensinogen; Asian People; China; Confidence Intervals; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetics, Population; Humans; Hypertension; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Publication Bias

The angiotensinogen (AGT) A-6G gene polymorphism has been indicated to be related to the susceptibility of essential hypertension. However, the results are still unclear.. To survey the relationship between AGT A-6G gene polymorphism and essential hypertension, 18 separate studies with 9306 patients were analyzed through meta-analysis. The random-effect model was used to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI).. In this AGT A-6G gene polymorphism and essential hypertension meta-analysis of the Chinese population, the distribution of the G-allele frequency was 0.23 for the essential hypertension group and 0.21 for the control group. The association between the AGT A-6G gene polymorphism and essential hypertension in the entire sample population was not significant. The pooled OR for the frequency of the G allele was 1.10 (95% CI 0.96 to 1.27, Pheterogeneity < 0.00001, P = 0.17). In the stratified analysis by ethnicity, a significant association in Li and Mongolian ethnicities (P ≤ 0.05) was achieved. However, no significant association was found in other ethnicities such as Han, Tibetan, Kazakh, Bai and Yi (P > 0.05).. The current meta-analysis suggested that AGT A-6G gene polymorphism might not be related to the increased risk of essential hypertension in the entire Chinese population. However, the G-allele of AGT A-6G might predispose to essential hypertension in the Li and Mongolian ethnicities.

Topics: Angiotensinogen; Asian People; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Genetic

The increased activity of intrarenal renin-angiotensin system (RAS) in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis and renal injury. Increases in intrarenal and interstitial angiotensin (Ang) II levels are due to increased AT(1) receptor mediated Ang II uptake and stimulation of renal angiotensinogen (AGT) mRNA and protein expression. Augmented proximal tubule AGT production increases tubular AGT secretion and spillover of AGT into the distal nephron and urine. Increased renin formation by principal cells of the collecting ducts forms Ang I from AGT thus increasing Ang II. The catalytic actions of renin and prorenin are enhanced by prorenin receptors (PRRs) on the intercalated cells. The resultant increased intrarenal Ang II levels contribute to the genesis of chronic hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Chronic Disease; Humans; Hypertension; Kidney; Kidney Tubules, Collecting; Prorenin Receptor; Receptors, Cell Surface; Renin

We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.

Topics: Alleles; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-1

Numerous studies in Chinese populations have evaluated the association between the A-6G and A-20C polymorphisms in the promoter region of angiotensinogen gene and hypertension. However, the results remain conflicting. We carried out a meta-analysis for these associations.. Case-control studies in Chinese and English publications were identified by searching the MEDLINE, EMBASE, CNKI, Wanfang, CBM, and VIP databases. The random-effects model was applied for dichotomous outcomes to combine the results of the individual studies. We finally selected 24 studies containing 5932 hypertensive patients and 5231 normotensive controls. Overall, we found significant association between the A-6G polymorphism and the decreased risk of hypertension in the dominant genetic model (AA+AG vs. GG: P=0.001, OR=0.71, 95%CI 0.57-0.87, P(heterogeneity)=0.96). The A-20C polymorphism was significantly associated with the increased risk for hypertension in the allele comparison (C vs. A: P=0.03, OR=1.14, 95%CI 1.02-1.27, P(heterogeneity)=0.92) and recessive genetic model (CC vs. CA+AA: P=0.005, OR=1.71, 95%CI 1.18-2.48, P(heterogeneity)=0.99). In the subgroup analysis by ethnicity, significant association was also found among Han Chinese for both A-6G and A-20C polymorphisms. A borderline significantly decreased risk of hypertension between A-6G and Chinese Mongolian was seen in the allele comparison (A vs. G: P=0.05, OR=0.79, 95%CI 0.62-1.00, P(heterogeneity)=0.84).. Our meta-analysis indicated significant association between angiotensinogen promoter polymorphisms and hypertension in the Chinese populations, especially in Han Chinese.

Topics: Adenine; Angiotensinogen; China; Ethnicity; Genetic Predisposition to Disease; Guanine; Humans; Hypertension; Polymorphism, Genetic; Promoter Regions, Genetic

The polymorphisms of angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes have been linked to increased risk of essential hypertension in multiple populations, but the results were inconsistent.. To evaluate the associations of these polymorphisms with essential hypertension, we carried out a meta-analysis of the association studies within Han Chinese population. In this study, we reviewed two most commonly investigated polymorphisms, AGT M235T and ACE I/D, and provided summary estimates regarding their associations with essential hypertension. PubMed and China Biological Medicine Database were searched, and a total of 71 studies (31 studies for AGT M235T and 40 studies for ACE I/D) comprising 10 547 essential hypertension patients and 9217 controls from 23 provinces and special districts in China were finally included in this study.. Statistically significant associations with essential hypertension were identified for TT genotype of AGT M235T polymorphism (odds ratio 1.54, 95% confidence interval 1.16-2.03, P = 0.002) and DD genotype of ACE I/D polymorphism (odds ratio 1.61, 95% confidence interval 1.32-1.98, P < 0.0001). Under dominant, recessive, and additive genetic models, positive associations were also found. The heterogeneity existed among the studies (P < 0.05), whereas the publication bias did not exist in both AGT analysis (P = 0.052) and ACE analysis (P = 0.103).. The present meta-analysis suggests that AGT M235T and ACE I/D modulate the risk of essential hypertension in Han Chinese population.

Topics: Angiotensinogen; China; Ethnicity; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin-angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of 'incomplete penetrance' through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating 'haplotypes'.

Topics: Angiotensinogen; Blood Pressure; Epidemiologic Methods; Genetic Predisposition to Disease; Humans; Hypertension; Peptidyl-Dipeptidase A; Renin-Angiotensin System

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Biomarkers; Humans; Hypertension; Kidney; Kidney Diseases; Peptidyl-Dipeptidase A; Prorenin Receptor; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Serine Proteases

Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin-angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin-angiotensin system blockers, and is compatible with the possibility that blocking local renin-angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Endothelium, Vascular; Humans; Hypertension; Renin; Renin-Angiotensin System; Risk Factors; Thromboplastin; Thrombosis

The knowledge of the genetic bases of hypertension has improved over the last decade; this area of research has high priority due to the high incidence of hypertension and its impact on public health. Monogenetic mineralocorticoid hypertension syndromes are associated with suppressed plasma renin activity due to excessive activation of the mineralocorticoid pathway. We review the pathophysiology, phenotype, and method of diagnosis for familial hyperaldosteronism type I and type II, hypertensive forms of congenital adrenal hyperplasia, 11beta-hydroxysteroid dehydrogenase type 2 deficiency, Liddle's syndrome, an activating mutation of the MR, and glucocorticoid resistance. We also review some genes that could contribute to essential hypertension.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; 11-beta-Hydroxysteroid Dehydrogenases; Adrenal Hyperplasia, Congenital; Angiotensinogen; Drug Resistance; Epithelial Sodium Channels; Glucocorticoids; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Excess Syndrome, Apparent; Peptidyl-Dipeptidase A; Phenotype; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Syndrome

Topics: Aldosterone; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Humans; Hypertension; Peptide Fragments; Peptidyl-Dipeptidase A; Prorenin Receptor; Receptors, Cell Surface; Receptors, Mineralocorticoid; Renin-Angiotensin System

Angiotensinogen (AGT) gene polymorphisms have been linked to increased risk of hypertension, but the data remain controversial. In this study we review the most commonly investigated polymorphisms at the AGT locus (other than M235T) and provide summary estimates regarding their association with essential hypertension, while addressing heterogeneity, as well as publication biases. Data on 26 818 subjects from 46 studies for the 4 most-studied AGT variants (T174M in exon 2 and 3 promoter variants: A-6G, A-20C, and G-217A) were meta-analyzed. Statistically significant associations with hypertension were identified for the T174M (odds ratio [OR]: 1.19; 95% CI: 1.07 to 1.33; P=0.002) and G-217A (OR: 1.37; 95% CI: 1.17 to 1.59; P=0.00006) polymorphisms. A dual but consistent effect was observed for the -20C allele, which was associated with a decreased risk of hypertension in populations of mixed and European ancestries (OR: 0.64; 95% CI: 0.44 to 0.92; P=0.02 and OR: 0.77; 95% CI: 0.65 to 0.91; P=0.003, respectively), but with a 24% increase in the odds of hypertension in Asian subjects (OR: 1.24; 95% CI: 1.04 to 1.48; P=0.02). No association of the A-6G variant with hypertension was detected. Current studies support the notion that single variants at the AGT might modulate the risk of hypertension but indicate caution in interpreting these results because of the putative presence of publication bias and gene-environment interactions.

Topics: Alleles; Angiotensinogen; Humans; Hypertension; Linkage Disequilibrium; Odds Ratio; Polymorphism, Single Nucleotide; Risk Factors

Genetic variation in the renin-angiotensin system (RAS) has been implicated in stroke, particularly the small vessel disease (SVD) subtype. Furthermore, there may be two distinct subtypes of cerebral SVD, isolated lacunar infarction (ILI) and ischaemic leukoaraiosis (ILA).. 300 patients with well-phenotyped SVD and 600 controls were genotyped for five polymorphisms in the angiotensinogen (AGT) gene and eight polymorphisms within the angiotensin-converting enzyme (ACE) gene.. AGT and ACE polymorphisms and haplotypes were no more common in SVD cases as a whole or the two subtypes. Amongst hypertensives only, an AGT promoter polymorphism (-20A-->C), was associated with the ILA subtype (multivariate odds ratio 1.716, 95% confidence interval 1.073-2.746, p = 0.024).. RAS genetic variants are not strong risk factors for cerebral SVD. The AGT -20C allele may be a risk factor for the leukoaraiosis subtype amongst hypertensives.

Topics: Angiotensinogen; Blood Vessels; Brain; Brain Infarction; Brain Ischemia; Case-Control Studies; Cerebrovascular Disorders; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Leukoaraiosis; Linkage Disequilibrium; Logistic Models; Odds Ratio; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Renin-Angiotensin System; Risk Assessment; Risk Factors; United Kingdom

In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Chronic Disease; Disease Models, Animal; Humans; Hypertension; Hypertension, Renal; Kidney; Kidney Diseases; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Nonmodulation is a process in which there is a disorder in angiotensin-dependent control of the renal circulation and adrenal aldosterone release. The abnormalities are associated with an inability to handle a sodium load and salt-sensitive hypertension. All of the features are corrected by angiotensin-converting enzyme inhibition. A striking family history of hypertension and concordance of responses to angiotensin II in sibling pairs have suggested a familial factor. Genes governing renin substrate (angiotensinogen) production showed gene polymorphisms in nonmodulators. As nonmodulation occurs in approximately 40% of patients with essential hypertension, clearly other genes must contribute.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Humans; Hypertension; Kidney; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renal Circulation; Renin; Renin-Angiotensin System; Sodium

Topics: Angiotensinogen; Biological Evolution; Blood Pressure; Humans; Hypertension; Renin-Angiotensin System

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Clinical Trials as Topic; Diet, Sodium-Restricted; Humans; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Pharmacogenetics; Polymorphism, Genetic; Weight Loss

Topics: Angiotensinogen; Animals; Genetic Therapy; Hepatocyte Growth Factor; Humans; Hypertension; Oligonucleotides, Antisense; Peptidyl-Dipeptidase A

Topics: Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Gene Expression Regulation; Humans; Hypertension; Kidney Diseases; Mutation; Polymorphism, Genetic; Promoter Regions, Genetic; Transcription, Genetic

Topics: Angiotensinogen; Animals; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Oligonucleotides, Antisense; Peptidyl-Dipeptidase A; Plasmids; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Viruses

Essential hypertension is a common, polygenic, complex disorder resulting from interaction of several genes with each other and with environmental factors such as obesity, dietary salt intake, and alcohol consumption. Since the underlying genetic pathways remain elusive, currently most studies focus on the genes coding for proteins that regulate blood pressure as their physiological role makes them prime suspects. The present study examines how polymorphisms of the insertion/deletion (I/D) ACE and M235T AGT genes account for presence and severity of hypertension, and embeds the data in a meta-analysis of relevant studies.. The I/D polymorphisms of the ACE and M235T polymorphisms of the AGT genes were determined by RFLP (restriction fragment length polymorphism) and restriction analysis in 638 hypertensive patients and 720 normotensive local blood donors in Weisswasser, Germany. Severity of hypertension was estimated by the number of antihypertensive drugs used.. No difference was observed in the allele frequencies and genotype distributions of ACE gene polymorphisms between the two groups, whereas AGT TT homozygotes were more frequent in controls (4.6% vs. 2.7%, P = .08). This became significant (p = 0.035) in women only. AGT TT genotype was associated with a 48% decrease in the risk of having hypertension (odds ratio: 0.52; 95% CI, 0.28 to 0.96), and this risk decreased more significantly in women (odds ratio: 0.28; 95% CI, 0.1 to 0.78). The meta-analysis showed a pooled odds ratio for hypertension of 1.21 (TT vs. MM, 95% CI: 1.11 to 1.32) in Caucasians. No correlation was found between severity of hypertension and a specific genotype.. The ACE I/D polymorphism does not contribute to the presence and severity of essential hypertension, while the AGT M235T TT genotype confers a significantly decreased risk for the development of hypertension in the population studied here. This contrasts to the findings of meta-analyses, whereby the T allele is associated with increased risk for hypertension.

Topics: Adult; Aged; Angiotensinogen; Cross-Sectional Studies; DNA Transposable Elements; Female; Gene Deletion; Gene Frequency; Genetic Predisposition to Disease; Genotype; Homozygote; Humans; Hypertension; Male; Methionine; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Severity of Illness Index; Threonine

Topics: Angiotensinogen; Animals; Humans; Hypertension

Topics: Aged; Aging; Angiotensinogen; Cytochrome P-450 CYP11B2; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Life Style; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Peptidyl-Dipeptidase A; Pharmacogenetics; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Topics: Angiotensinogen; Animals; DNA-Binding Proteins; Evolution, Molecular; Haplotypes; Humans; Hypertension; Kidney Tubules; Mutation, Missense; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Transcription Factors; Transcription, Genetic; Upstream Stimulatory Factors

Topics: 11-beta-Hydroxysteroid Dehydrogenases; ACTH Syndrome, Ectopic; Adenoma; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Angiotensinogen; Cushing Syndrome; Diagnosis, Differential; Glucocorticoids; Humans; Hydrocortisone; Hypertension; Nitric Oxide; Pituitary Neoplasms; Receptor, Angiotensin, Type 1; Sympathetic Nervous System

Topics: Angiotensinogen; Genetic Predisposition to Disease; Genomics; Haplotypes; Humans; Hypertension; Phenotype

Hypertension is a common trait worldwide and is responsible for a major expenditure of health-care dollars in the United States. Although the etiological factors responsible for the expression of this phenotype are complex, several experimental and clinical observations point to a major role of the kidney as responsible. Genetic studies of uncommon diseases, which express monogenetic inheritance, all have in common a dysregulation of sodium balance and volume expansion. Furthermore, epidemiological data suggest an increased incidence of hypertension in communities with high excretory rates of sodium. Experimental data also suggest that low birth weight is associated with an increase in the frequency of hypertension later in life and raises the possibility that intrauterine imprinting may contribute to the expression of the phenotype. Indeed, data suggesting up-regulation of the Na(+)/K(+)/2Cl(-) and thiazide-sensitive transporters in low-birth-weight animals may provide the physiological basis for these observations. Finally, subtle gain of function mutations in one or more of these transporters may unmask defects in volume homeostasis with increasing salt intake.

Topics: Angiotensinogen; Animals; Extracellular Fluid; Homeostasis; Humans; Hypertension; Kidney; Receptors, Mineralocorticoid; Sodium

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Humans; Hypertension; Juxtaglomerular Apparatus; Kidney; Kidney Tubules; Nitric Oxide; Renin-Angiotensin System

Arterial hypertension is one of the major cardiovascular risk factors in Western countries. Besides some well established, but rather rare forms of secondary hypertension, essential hypertension is the most common diagnosis. The hereditary nature of this disease has been well established in many familial studies. The quantitative contribution of genetic factors to blood pressure variance is estimated to be about 30%, however, the genetic background of essential hypertension is complex and currently not fully understood. Besides few monogenetic forms of Mendelian transmitted hypertension, current efforts are usually directed at the identification of single contributing genetic factors. This review is thought to highlight current strategies towards a better understanding of the genetic background of essential hypertension with particular respect to genetic variants of the renin-angiotensin system, of signaling pathways such as heterotrimeric G-proteins and alpha-adducin. Moreover, genetic association studies often fail to replicate findings from previous studies. This may be in part due to the polygenetic nature of the disease. Another potential reason may be the diversity of the investigated populations. The current results of genetic analyses of essential hypertension highlight, thus, the need for a more differentiated approach to the understanding of complex, polygenetic traits implementing gene-gene-, and gene-environment interactions or distinguished functional testing of thoroughly phenotyped cohorts under standardised environmental conditions.

Topics: Alleles; Angiotensinogen; Blood Pressure; Calmodulin-Binding Proteins; Case-Control Studies; Environment; Genetic Linkage; GTP-Binding Proteins; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors

Overfeeding of rodents leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes. Whereas angiotensin II promotes adipocyte growth and preadipocyte recruitment, increased secretion of angiotensinogen from adipocytes also directly contributes to the close relationship between adipose-tissue mass and blood pressure in mice. In contrast, angiotensin II acts as an antiadipogenic substance in human adipose tissue, and the total increase in adipose-tissue mass may be more important in determining human plasma angiotensinogen levels than changes within the single adipocyte. However, as increased local formation of angiotensin II in adipose tissue may be increased especially in obese hypertensive subjects, a contribution of the adipose-tissue renin-angiotensin system to the development of insulin resistance and hypertension is conceivable in humans, but not yet proven. Insulin resistance may be aggravated by the inhibition of preadipocyte recruitment, which results in the redistribution of triglycerides to the liver and skeletal muscle, and blood pressure may be influenced by local formation of angiotensin II in perivascular adipose tissue. Thus, although the mechanisms are still speculative, the beneficial effects of ACE-inhibition and angiotensin-receptor blockade on the development of type 2 diabetes in large clinical trials suggest a pathophysiological role of the adipose-tissue renin-angiotensin system in the metabolic syndrome.

Topics: Adipocytes; Adipose Tissue, Brown; Angiotensin II; Angiotensinogen; Animals; Humans; Hypertension; Insulin Resistance; Metabolic Syndrome; Mice; Obesity; Peptidyl-Dipeptidase A; Rats; Renin; Renin-Angiotensin System; Thermogenesis

The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations.. One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%; P=0.0004) in MT heterozygotes and 11% (7% to 15%; P<0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.. Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.

Topics: Angiotensinogen; Asian People; Black People; Blood Pressure; Genotype; Heterozygote; Homozygote; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Polymorphism, Genetic; Stroke; White People

Excess salt intake is an important environmental risk for the predisposition to essential hypertension. Previous physiological studies have shown that salt sensitivity is associated with insulin resistance, enhancement of sympathetic nerve activity and decrease of blood pressure decline at night. We have been examining the genetic importance of candidate gene polymorphisms of salt-sensitive hypertension using several populations. The angiotensinogen gene (AGT) is a thrifty gene which increases the risk for common disease with growth of civilization via sodium and body fluid retention. The CC genotype of the AGT/T+31C polymorphism, which is in complete linkage disequilibrium with the TT genotype of the M235T polymorphism, was associated with a decrease of blood pressure decline at night in the Ohasama Study. On the other hand, the Gly460Trp genotype of the alpha-adducin gene (ADD1) is associated with erythrocyte sodium transport and increases tubular sodium reabsorption and risk for hypertension. We also revealed in the Ohasama Study that the Trp460 allele of ADD1 is associated with hypertension in young subjects with low renin activity. In addition to these polymorphisms, the T(-344)C polymorphism in the promoter of the aldosterone synthase gene (CYP11B2) and the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) are considered candidates for the genetic risk of salt-sensitive hypertension. We compared the allele frequency of five candidate genes between Japanese and Caucasians; the results showed that the frequencies of all alleles were significantly higher in Japanese than in Caucasians. This interesting finding might suggest a feasible explanation for the huge interracial differences in the frequency of salt-sensitive hypertension.

Topics: Angiotensinogen; Asian People; Calmodulin-Binding Proteins; Cytochrome P-450 CYP11B2; Genotype; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Japan; Polymorphism, Genetic; Sodium Chloride, Dietary

Essential hypertension affects up to 30% of the adult population; its pathogenesis involves interactions between genetic and environmental factors. Improved understanding of the molecular basis of essential hypertension may facilitate the development of new targeted forms of pharmacological therapy that can be tailored to the needs of individual patients and thereby minimize the risk of morbidity and mortality from cardiovascular diseases. The genetic analysis of complex traits and diseases such as blood pressure and hypertension is difficult because of their polygenic origin, genetic heterogeneity, variable penetrance, unknown modes of inheritance, and variable effects of environmental factors. Molecular variants of the angiotensinogen (AGT) gene, a key component of the renin-angiotensin system, are considered a genetic risk for primary hypertension. Some of the genotypes can be used to identify individual patients who would benefit from a specific anti-hypertensive treatment as well as from a specific life style modification.

Topics: Angiotensinogen; Calmodulin-Binding Proteins; Cardiovascular Diseases; Genotype; Humans; Hypertension; Life Style; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-3; Risk

Topics: Angiotensinogen; Genetic Techniques; Humans; Hypertension; Linkage Disequilibrium; Polymorphism, Single Nucleotide

To study on the association of M235T polymorphism of the angiotensinogen gene extron 2 (AGT/M235T) and essential hypertension (EH) in Chinese population by means of Meta-analysis.. Odds ratios (OR) of AGT M235T genotype distributions in EH patients against healthy controls were analyzed. All the relevant studies were identified, poor-qualified studies eliminated, and the risk of publication bias excluded. The Meta-analysis software, REVMAN4.1, was applied for investigating heterogeneity among individual studies and summarizing the effects across studies.. A total of 853 cases and 835 controls from 10 studies were included. No heterogeneity among the studies was noticed. The frequencies of the AGT TT, MT and MM genotypes were 65%, 30%, and 4.9% in cases and 50.6%, 41.8% and 7.5% in controls respectively. The frequencies of the AGT T allele were 80% in cases and 72% in controls. The pooled OR (with 95% CI) of TT vs MT + MM was 1.76 (1.44 - 2.16) (P < 0.000 01) with T vs M 1.54 (1.31 - 1.81). The pooled OR of MM vs MT + TT was 0.67 (0.45 - 1.00) (P = 0.05).. In Chinese population (mainly the Hans), TT genotype might be associated with the increased risk of EH while MM genotype be associated with low risk of EH.

Topics: Alleles; Angiotensinogen; Blood Pressure; China; Exons; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Odds Ratio; Polymorphism, Genetic; Renin-Angiotensin System

The extent of blood pressure lowering by anti-hypertensive agents is difficult to predict for individual patients, even when evaluated in the context of biochemical or demographic information. Genetic predictors (mainly single nucleotide polymorphisms, SNPs) have been the focus of several recent studies and are gaining much attention. We have conducted a literature search for studies in which the lowering of ambient blood pressure by specific drugs or drug classes in humans was related to specific genotypes. Twenty-eight studies were identified, of which six had a single-dose design, and the remaining 22 studied drug effects after more than 4 weeks of drug administration. Virtually all were association studies. Prospective trials that compared the prognostic value of genetic methods to routine clinical practice were not identified. Almost all studies used a candidate-gene design, usually with a very small number of SNPs (typically one). Gene-gene and gene-environment interactions were studied only rarely. Only one study targeted genes involved in drug metabolism. Most candidate-genes were part of the renin-angiotensin system. By far the most extensively studied has been the angiotensin-converting enzyme insertion/deletion polymorphism (15 studies) but, to date, no clear picture has emerged for this or other genetic variants. Thus, the potential for utility of genetic characterization of individual patients as a predictor of anti-hypertensive response has yet to be realized.

Topics: Angiotensinogen; Calmodulin-Binding Proteins; GTP-Binding Proteins; Humans; Hypertension; Peptidyl-Dipeptidase A; Pharmacogenetics; Polymorphism, Genetic; Receptors, Adrenergic, beta-1; Receptors, Angiotensin

Hypertension is considered to be a complex trait to which genetic, environmental, and demographic factors contribute interactively. Recently, molecular genetic studies have achieved remarkable success in the elucidation of causative mutations in several Mendelian hypertensive disorders in which single nucleotide polymorphisms (SNPs) disrupt the function of single genes, thereby leading to unambiguous phenotypes. It seems unlikely, however, that such a simple base-substitution is the primary mechanism in cases of essential hypertension, even if SNPs modify the relevant gene function to some extent. Despite the enormous efforts made to date, no consistent association between any of the candidate genes and essential hypertension has been established. One plausible explanation is that because individual genes play a modest role in the pathogenesis of hypertension, confounding variables, whether individual (sex, ethnic origin, etc.) or environmental, may decrease the chance of identifying a causative relation between the genes and hypertension, depending on the populations studied. Several approaches can be proposed to overcome this problem, including long-term follow-up of clinical events collected to attain sufficient phenotypic information and statistical power. With the recent advances in high-throughput genotyping techniques and bioinformatic strategies, it has become possible to perform even SNP-based genome-wide screening. At present, however, the need for identification of susceptibility genes for hypertension still poses a great and unanswered challenge. Nonetheless, we believe that a precise understanding of the manner in which genetic variations affect hypertension can be achieved, and that clarification of the associated phenotypes will lead to the development of effective preventive and treatment strategies.

Topics: Angiotensinogen; Animals; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 5; Genetic Linkage; Humans; Hypertension; Peptidyl-Dipeptidase A; Rats; Receptors, Adrenergic, beta-3

African Americans shoulder a disproportionately high burden of kidney disease when compared with white Americans. While environmental factors such as poverty and poor health habits, and the high prevalence of risk factors such as obesity, contribute to the high rate of kidney disease in this population, genetic factors may also contribute. Studies of polymorphisms in genes encoding the proteins of the renin-angiotensin-aldosterone system have identified alleles that are associated with kidney disease or changes in renal function in some populations. A higher prevalence of such alleles in African Americans may contribute to the increased prevalence of kidney disease. Diabetes mellitus and hypertension, the main causes of end-stage renal disease in the United States, are more prevalent in African Americans. However, no direct links between diabetic or hypertensive kidney disease and any genetic polymorphisms seen in African Americans have been identified. Further research is thus required to elucidate the genetic components that contribute to the high prevalence of kidney disease in African Americans.

Topics: Angiotensinogen; Black or African American; Black People; Diabetic Nephropathies; Humans; Hypertension; Kallikreins; Kidney Failure, Chronic; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prevalence; Renin-Angiotensin System; United States

Topics: Angiotensinogen; Animals; Cardiovascular Diseases; Gene Targeting; Humans; Hypertension; Mice; Mice, Knockout; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Intrarenal angiotensin II (Ang II) is regulated by several complex processes involving formation from both systemically delivered and intrarenally formed substrate, as well as receptor-mediated internalization. There is substantial compartmentalization of intrarenal Ang II, with levels in the renal interstitial fluid and in proximal tubule fluid being much greater than can be explained from the circulating levels. In Ang II--dependent hypertension, elevated intrarenal Ang II levels occur even when intrarenal renin expression and content are suppressed. Studies in Ang II--infused rats have demonstrated that augmentation of intrarenal Ang II is due, in part, to uptake of circulating Ang II via an Ang II type 1 (AT(1)) receptor mechanism and also to sustained endogenous production of Ang II. Some of the internalized Ang II accumulates in the light and heavy endosomes and is therefore potentially available for intracellular actions. The enhanced intrarenal Ang II also exerts a positive feedback action to augment intrarenal levels of angiotensinogen (AGT) mRNA and protein, which contribute further to the increased intrarenal Ang II in hypertensive states. In addition, renal AT(1) receptor protein and mRNA levels are maintained, allowing increased Ang II levels to elicit progressive effects. The increased intrarenal Ang II activity and AGT production are associated with increased urinary AGT excretion rates. The urinary AGT excretion rates show a clear relationship to kidney Ang II content, suggesting that urinary AGT may serve as an index of Ang II--dependent hypertension. Collectively, the data support a powerful role for intrarenal Ang II in the pathogenesis of hypertension.

Topics: Angiotensin II; Angiotensinogen; Humans; Hypertension; Kidney; Kidney Tubules; Receptors, Angiotensin

Topics: Angiotensinogen; Antihypertensive Agents; Cytochrome P-450 CYP11B2; Genetic Markers; Humans; Hypertension; Hypertrophy, Left Ventricular; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors

Hypertension is a disease caused by multiple genes. The traditional treatments have many defects. A gene therapy has been proposed where antisense oligonucleotide (AS ODN) is developed to specifically block the expression of hypertension candidate genes. It is of long-term effect, high efficiency and non toxicity. Preliminary results are encouraging, but much work needs to be done before gene therapy could be applied to humans.

Topics: Angiotensinogen; Animals; Genetic Therapy; Humans; Hypertension; Oligonucleotides, Antisense; Peptidyl-Dipeptidase A; Renin

Topics: Angiotensin II; Angiotensinogen; Humans; Hypertension; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

There is general consensus that genetic variation accounts in part for individual susceptibilities to essential hypertension. In marked contrast to classic mendelian disorders, in which genetic alterations produce a gain or loss of function, genetic determinants of essential hypertension, high blood pressure of unknown cause, are expected to be small, achieving significance through the cumulative effects of environmental exposure over the course of a lifetime. Whether and how genetic factors that contribute to common diseases can be identified remain unclear. Research on a link between angiotensinogen and essential hypertension illustrates a path that began in genetics and is now leading toward nephrology. Various challenges encountered along the way may prove to be characteristic features of genetic investigations of the pathogenesis of common diseases. The implication of a gene by statistical analysis is only the beginning of a protracted process of functional analysis at increasing levels of biologic integration. The ultimate goal is to develop an understanding of the manner in which genetic variation at a locus can affect a physiologic parameter and to extract from this inference new knowledge of significance for the prevention or treatment of disease.

Topics: Alleles; Angiotensin II; Angiotensinogen; Female; Genetic Linkage; Genetic Variation; Haplotypes; Homeostasis; Humans; Hypertension; Japan; Male; Models, Genetic; Nephrons; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Promoter Regions, Genetic; Renin-Angiotensin System

Gene therapy for hypertension is very important for the next generation of antihypertensive drugs. Important question regarding vector-related limitations and suboptimal in vivo delivery systems will require expeditious attention for gene therapy to become a more widely applicable option in cardiovascular diseases including hypertension. However, the elucidation of molecular mechanisms of transcriptional activation of several important genes in the cardiovascular physiology enables us to develop clinical application of gene therapy for hypertension at the level of transcription factors. Recent studies showed that in vivo or ex vivo transfection of double-stranded oligodeoxynucleotides to block the binding of nuclear factors to specific cis-elements in the promoter regions of several genes resulted in inhibition of gene trans-activation and suppressed pathological changes in the cardiovascular system.

Topics: Angiotensinogen; Animals; Carrier Proteins; Cell Cycle Proteins; DNA-Binding Proteins; E2F Transcription Factors; Gene Transfer Techniques; Genetic Therapy; Humans; Hypertension; Oligodeoxyribonucleotides; Promoter Regions, Genetic; Retinoblastoma-Binding Protein 1; Transcription Factor DP1; Transcription Factors; Transcriptional Activation; Transfection

Under classical strategy, scientists have tried first to find a physiological phenomenon specific for essential hypertension, then to identify the protein underlying the physiological abnormality, and finally to clarify the causative gene which encoded the protein. On the other hand, under the reverse genetic approach, the correlation between hypertension and genetic abnormality is identified first, and then the pathogenesis is clarified-in reverse order. Therefore, it is not extraordinary for unexpected results to be obtained in the correlation between a gene and a disease, suggesting that this approach has a possibility to be a breakthrough in the chaos of hypertension research.

Topics: Angiotensinogen; Animals; Asian People; Disease Models, Animal; Gene Expression Regulation; Genetic Linkage; Genetic Predisposition to Disease; Genetic Therapy; Humans; Hypertension; Liposomes; Oligodeoxyribonucleotides, Antisense; Polymorphism, Restriction Fragment Length; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Transfection; White People

Topics: Aged; Aging; Angiotensinogen; Female; Humans; Hypertension; Male; Peptidyl-Dipeptidase A

Essential hypertension is a multifactorial disease which is evoked by multiple environmental and genetic factors. Recent progress in molecular biology enables us a comprehensive understanding of the molecular pathogenesis of this disease. The genes of renin-angiotensin system such as renin, angiotensinogen, angiotensin-converting enzyme and angiotensin receptors genes are all reported as positive linkage to hypertension. Now ongoing progress of the human genome project will further accelerate the molecular studies on the rennin-angiotensin system and hypertension.

Topics: Angiotensinogen; Animals; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Essential hypertension illustrates the formidable task presented by the identification of genetic determinants of common disease. Making an initial genetic inference may prove difficult enough; the subsequent demonstration of functional significance at various levels of biological integration may be even more challenging. We review three instances in which an initial genetic inference has led to the development of testable hypotheses pursued at increasingly higher levels of biological organization. These include the adducin, the G protein beta3 subunit, and the angiotensinogen hypotheses.

Topics: Angiotensinogen; Animals; Calmodulin-Binding Proteins; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Models, Genetic; Protein Subunits

Gene therapy for hypertension is needed for the next generation of antihypertensive drugs. Current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day). Gene therapy offers a way to produce long-lasting antihypertensive effects (weeks, months or years). We are currently using two strategies: antisense oligodeoxynucleotides (AS-ODN), an dantisense DNA delivered in viral vectors, to inhibit genes associated with vasoconstrictive properties. It is not necessary to know all the genes involved in hypertension, since many years of experience with drugs show which genes need to be controlled. AS-ODNs are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODNs, targeted to AT1 receptors (AT1R), angiotensinogen (AGT), angiotensin converting enzyme (ACE) and beta 1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C and cold-induced) hypertension. The effects can last up to one month when delivered with liposomes. No side effects or toxic effects have been detected and repeated injections can be given. For the vector, adeno-associated virus (AAV) is used with a construct to include a CMV promoter, antisense DNA to AGT or AT1R and a reporter gene. Results in SHR demonstrate reduction and slowing of hypertension development with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AS-AGT treatment. Double transgenic mice (human renin plus human AGT) with high angiotensin II (Ang II) causing high blood pressure, treated with AAV-AT1R-AS, show a normalisation of blood pressure for over 6 months with a single injection of vector. We conclude that ODNs will probably be developed first because they can be treated like drugs for the treatment of hypertension with long-term effects. Viral vector delivery needs more engineering to be certain of its safety but one day may be used for a very prolonged control of blood pressure.

Topics: Angiotensinogen; Animals; Dependovirus; DNA, Antisense; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Liposomes; Oligodeoxyribonucleotides, Antisense; Plasmids

Essential hypertension is a complex disease influenced by different genetic and environmental factors. The renin-angiotensin system (RAS) is implicated in blood pressure regulation. Angiotensinogen (AGT) is the precursor of the biologically active angiotensin II (Ang II). Initial studies on hypertensive siblings and case-control studies indicated the important role of the angiotensinogen gene (AGT) for the predisposition to essential hypertension, preeclampsia and obesity-related hypertension. Recently, different AGT polymorphisms had been identified and analyzed in case-control studies. The aim of present studies is the analysis of potentially functional AGT variants (C-532T, G-6A), which might be responsible for the regulation of gene expression and therefore AGT generation. The A-6 allele is in complete linkage disequilibrium with the T235 allele and is associated with higher AGT expression in vitro. Segregation linkage analysis demonstrated that the C-532T polymorphism influences plasma AGT variability more significantly than the G-6A variant. Since the C-532T polymorphism is located within a AP-2 consensus element, functional promoter analyses are required. The understanding of the molecular basis of RAS in essential hypertension may provide us with new and more specific pharmacological agents and perhaps the ability to individualize antihypertensive treatment.

Topics: Alleles; Angiotensinogen; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Hypertension; Linkage Disequilibrium; Obesity; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy

In the past year, substantial progress has been made in both mapping and fine mapping the genes involved in blood pressure regulation. Genome scans have been carried out in humans and mice and these reveal many new potential chromosomal locations for blood pressure susceptibility loci. The chromosomal regions containing blood pressure genes for many of the inbred hypertensive rat models have been refined using new congenic strains. Further genetic studies support a role for antiotensinogen, aldosterone synthase and a region close to the epithelial sodium channel in blood pressure regulation. Finally, comprehensive single-nucleotide polymorphism analysis of cardiovascular genes has been undertaken using chip technology.

Topics: Angiotensinogen; Animals; Cytochrome P-450 CYP11B2; Epithelial Sodium Channels; Genome, Human; Humans; Hypertension; Mice; Rats; Rats, Inbred SHR; Sodium Channels

Since the discovery of renin by Tigerstedt and Bergmann, the renin angiotensin system (RAS) has been recognized as an important modulator of blood pressure and volume homeostasis. Based on these functions a pathophysiological role of the RAS in the pathogenesis of hypertension and other cardiovascular disorders has been postulated. The therapeutic benefit of RAS inhibition by angiotensin converting enzyme (ACE) inhibitors and angiotensin II (ANG II) antagonists in these conditions has been shown. It remains unclear, however, whether the changes in RAS activity associated with cardiovascular disease are primary or secondary factors. It is well known that hypertension and hypertensive end-organ disease is influenced by genetic factors. Gene polymorphisms for virtually all components of the RAS have been described and investigated in clinical studies. It remains to be determined, however, how relevant these findings are for disease etiology. This review, therefore, will attempt to discuss the causal implications of these genetic studies for cardiovascular disease. The role of angiotensinogen and ACE for hypertension, coronary artery disease and other cardiovascular disorders is discussed in this context in an exemplary fashion.

Topics: Angiotensinogen; Animals; Coronary Disease; Genetic Predisposition to Disease; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System

Topics: Angiotensinogen; Diet, Sodium-Restricted; Humans; Hypertension

The generation of knockout mice using homologous recombination in embryonic stem cells is a powerful tool for physiologic investigations. This experimental approach has provided unique insights into the study of hypertension. Studies using knockout mice have shed new light on blood pressure regulatory mechanisms, molecular mechanisms of end-organ injury, and genetic mechanisms for hypertension. With the development of more accessible approaches for carrying out sophisticated manipulation of the mouse genome, there will be continuing utility of this technique for future studies of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Disease Models, Animal; Gene Expression; Humans; Hypertension; Mice; Mice, Knockout; Phenotype; Receptors, Angiotensin; Renin-Angiotensin System; Stem Cells

Essential hypertension is an insidious disease in which the afflicted person risks disability and death from myocardial infarction and stroke. Many factors contribute to the development of essential hypertension, including environment, diet, daily stress, and genetics. Although several single gene disorders causing high blood pressure have been identified, the genetics of essential hypertension are much more complicated. The current hypothesis is that a combination of genetic variations in multiple genes may predispose a person to hypertension. Both overexpression and gene inactivation ("knockout") have proven useful tools to evaluate the genetics of essential hypertension and to identify pathways regulating blood pressure. Molecular and physiologic evaluations of transgenic and knockout mice carried out over the past 5 years have provided a plethora of information about the mechanisms of blood pressure regulation and the development and maintenance of hypertension. This review focuses on the newer mouse models that have been developed to investigate hypertension with an emphasis on vascular and renal mechanisms, contributed by the renin-angiotensin system, and other pathways intersecting with the renin-angiotensin system.

Topics: Angiotensin II; Angiotensinogen; Animals; Disease Models, Animal; Humans; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Peptidyl-Dipeptidase A; Receptors, Dopamine; Receptors, Neuropeptide; Renin-Angiotensin System

Topics: Angiotensinogen; Animals; Humans; Hypertension

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-beta and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model. We speculate that the transcription factors NFkappaB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Coronary Circulation; Humans; Hypertension; Kidney; Models, Cardiovascular; Myocardium; Rats; Renal Circulation; Renin

The candidate gene approach to understanding the genetics of human essential hypertension is discussed by analyzing the contribution of 2 genes, angiotensinogen (AGT) and epithelial amiloride-sensitive sodium channel (ENaC). From a large series of studies conducted in humans and animals, it appears that the AGT gene plays a significant but modest role in human blood pressure variance. Mutations of the beta- and gamma-ENaC subunits are responsible for Liddle's syndrome, but the implication of the 3 ENaC subunits in essential hypertension is still questionable. Several lessons can be learned from these studies and applied to other candidate genes in essential hypertension: (1) Many linkage or association studies have a limited statistical power; (2) The genetic findings may vary greatly according to the populations studied; (3) There is a need for better phenotyping of the hypertensive population; (4) The causal relationship between molecular variants and hypertension is and will be difficult to establish firmly; (5) The contribution of genetic studied in rodents to the molecular genetics of human hypertension must be re-examined; (6) Most molecular variants lead to a low attributable risk in the population or a low individual effect at the individual level; and (7) It is too early to propose dietary recommendations and specific drug treatment according to patients' genotypes.

Topics: Angiotensin II; Angiotensinogen; Animals; Diet; Diet, Sodium-Restricted; Epithelial Sodium Channels; Genetic Variation; Genotype; Humans; Hypertension; Rats; Renal Circulation; Sodium Channels

Blood pressure homeostasis in humans reflects the coordinate interactions of cardiac output, peripheral vascular resistance, renal volume control, and CNS integration in response to short- and long-term environmental stimuli. Variations in mean arterial pressure within the population include a significant hereditary component. The clearest examples of this genetic contribution occur in rare forms of monogenic hypertension (glucocorticoid remediable aldosteronism, apparent mineralocoid excess, Liddle's syndrome) or hypotension (pseudohypoaldosteronism type I, Bartter's syndrome, Gitelman's syndrome). Primary hypertension, which comprises approximately 95% of hypertensives and is a major risk factor for coronary heart disease, stroke, and renal disease in the U.S., represents a multifactorial and polygenic disease with incremental contributions from genetic and environmental determinants. Efforts to date have identified several candidate genes involved in primary hypertension, including angiotensinogen (AGT), a vasoactive peptide; alpha-adducin, a protein that regulates sodium transport; and the G protein beta 3 subunit, a protein involved in intracellular signal transduction. Advances in knowledge and technology associated with the Human Genome Project, combined with continuing basic research on the physiologic and biochemical causes of hypertension, offer promise for improved diagnosis and therapy of this prevalent disease.

Topics: Angiotensinogen; Blood Pressure; Calmodulin-Binding Proteins; GTP-Binding Proteins; Homeostasis; Human Genome Project; Humans; Hypertension; Renin-Angiotensin System

Accumulating evidence has supported the pathophysiological role of angiotensinogen in essential hypertension. However, some studies of molecular genetics have implicated that there may be an ethnic variation concerning the disease susceptibility of the AGT gene.. To evaluate the importance of this candidate gene for hypertension, we undertook an extensive association study in the Japanese. This case-control study was conducted in a total of 1232 individuals consecutively enrolled in a single institution, divided into two subgroups: one subgroup comprised 254 hypertensive and 224 normotensive subjects and the other comprised 463 hypertensive and 291 normotensive subjects. A meta-analysis was subsequently performed on six Japanese studies including the present study.. No significant association was observed between a molecular variant of AGT, Thr235, and hypertension status in our case-control study. Moreover, this finding was extendible to another AGT polymorphism, G-6A, one of the potential functional polymorphisms in the promoter region, because these two polymorphisms proved to be in complete linkage disequilibrium in the studied population. The meta-analysis revealed that the pooled estimate of the odds ratio across the studies was 1.22 (95% CI 1.05-1.42), and that there was significant evidence against homogeneity of the odds ratios among the studies included (phi2 = 19.8, df = 5, P = 0.0014). In particular, a large range of variation (60-83%) was found for the allele frequency of Thr235 among control subjects of the six Japanese case-control studies.. Although the meta-analysis appears in favour of association between the AGT variant and essential hypertension in the Japanese, there is considerable heterogeneity among the studies and the evidence is also rather borderline. Further comprehensive approaches are needed to resolve this debatable issue.

Topics: Adult; Angiotensinogen; Blood Pressure; DNA; Female; Genotype; Humans; Hypertension; Japan; Linkage Disequilibrium; Male; Middle Aged; Odds Ratio; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic; Retrospective Studies

Topics: Acetylcholinesterase; Angiotensinogen; Humans; Hypertension; Mutation

Topics: Angiotensinogen; Humans; Hypertension; Mutation; Renin-Angiotensin System

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Risk Factors

Topics: Angiotensinogen; Calmodulin-Binding Proteins; Disease Models, Animal; Humans; Hypertension; Peptidyl-Dipeptidase A; Renin

According to the "thrifty-genotype" hypothesis proposed by Neel, diseases of civilization such as non-insulin-dependent diabetes mellitus and hypertension result from a discordance between certain features of our present-day environment and our genetic make-up which evolved to fit the life of Paleolithic humans. This concept implies that while "affected" individuals harbor the "original" ancestral version of the relevant genes, healthy or "unaffected" individuals have picked up recent mutations leading to a "loss of thriftiness" of these genes. Support for this concept now comes from recent studies of the angiotensinogen gene, where an ancestral variant of the gene (AGT 235T), also present in primates, has now been associated with hypertension whereas a neomorphic variant (AGT 235M) apparently reduces the risk of high blood pressure. The implications of these findings for our understanding and approach to the study of complex genetic diseases is discussed.

Topics: Angiotensinogen; Animals; Biological Evolution; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genetic Variation; Hominidae; Humans; Hypertension; Primates

Essential hypertension results from the interaction of genetic and environmental factors. To date progress has mainly concerned rare genetic forms of hypertension, but molecular advances and current large collaborative studies make it likely that common genetic factors in hypertension will soon be determined.

Topics: Angiotensinogen; Blood Pressure; Genetic Linkage; Genome, Human; Humans; Hypertension; Phenotype

The renin-angiotensin system (RAS) has been extensively studied in the past decades as an important mediator of hypertension and hypertensive end-organ damage. Originally, the RAS was described as an endocrine system that exerts its action through the effector peptide angiotensin II (ANG II). Recently, tissue-based renin-angiotensin systems which act through paracrine-autocrine mechanisms have been suggested as the more important pathway. After all, genes of the RAS have been cloned transgenic animals overexpressing different components of the RAS were constructed. Furthermore, gene polymorphisms were investigated as genetic markers for hypertension and cardiovascular disease. Finally, very effective substances interacting on different levels of the RAS cascade were developed.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Genetic Techniques; Humans; Hypertension; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System

For the past decade, hypertension research has shifted strongly in the direction of molecular genetics. The success stories are the monogenic hypertensive syndromes. Classic linkage analyses has located the responsible genes for glucocorticoid-remediable aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess. The genes have been cloned and their function elucidated. Other monogenic syndromes are currently being intensively studied. However, in the area of primary hypertension, the successes have relied on the candidate gene approach. Allelic variants in the genes for angiotensinogen, alpha-adducin, beta2-adrenergic receptor, the G-protein beta3-subunit and the T594M mutation in the beta-subunit of the epithelial sodium channel have been identified; however, the importance of these allelic variants to primary hypertension as a whole, is not yet clear. A variant in the angiotensin-converting enzyme gene could not, initially, be convincingly associated with hypertension, but more recent analyses suggest an influence of the deletion allele on blood pressure in men, but apparently not in women. In all likelihood we are dealing with many genes with small effects. Affected sibling pair linkage analyses will probably not be successful in identifying the loci of these genes. To find new genes, novel approaches will be necessary, including searching for quantitative trait loci linked to blood pressure in normotensive persons, haplotype sharing methodology in trios and family units, the use of better study designs, and the investigation of isolated populations. Finally, rethinking the phenotype 'hypertension' and its intermediates must also receive priority.

Topics: Angiotensinogen; Calmodulin-Binding Proteins; Female; Fingers; GTP-Binding Proteins; Humans; Hyperaldosteronism; Hypertension; Male; Mineralocorticoids; Molecular Biology; Mutation; Peptidyl-Dipeptidase A; Receptors, Adrenergic, beta-2; Sodium Channels; Syndrome

An update on renal genetic mechanisms of spontaneous hypertension in rats and in human essential hypertension is presented. The findings are discussed, highlighting the search of a possible link between the discovered genetic abnormality and the renal function changes that may determine the disease. The analogies (and/or differences) between the numerous positive findings obtained in animal models and the relatively scarce ones obtained in humans are discussed.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Calmodulin-Binding Proteins; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Endothelins; Family; Humans; Hypertension; Mixed Function Oxygenases; Models, Cardiovascular; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor; Renin; Sodium Channels

In the most exciting genetic advances in the diagnosis of essential hypertension, genes responsible for three distinct forms of low-renin hypertension have been identified. Two of these forms are dominant: glucocorticoid remediable hypertension (a new gene created by the fusion of the 11 beta-hydroxylase and aldosterone synthase genes) and Liddle's syndrome (a defect in the epithelial sodium channel). One of the forms is recessive: the syndrome of apparent mineralocorticoid excess (a defect in renal 11 beta-hydroxysteroid dehydrogenase). The role of more than 20 other genes in causing hypertension has been assessed with variable findings. The most convincing evidence supports a role for the angiotensinogen gene, where linkage has been documented and an association with an intermediate phenotype of hypertension (nonmodulation) has been reported.

Topics: Angiotensinogen; Animals; Genetic Linkage; Humans; Hypertension; Peptidyl-Dipeptidase A; Phenotype; Renin-Angiotensin System; Syndrome

The advancement of molecular biomedical techniques has allowed solutions to the problem of finding a genetic linkage to hypertension. This is now being approached by limiting study to a select number of genetic factors possibly influencing a particular physiologic dysfunction or structural defect. Analysis of chromosomal abnormalities or regions bearing a particular mutation have been greatly influenced by the ability to produce artificial chromosomes or to identify closely linked markers. Rapid accumulation of knowledge of the genetic map has led to a number of these gene/disease linkages. Perhaps the unraveling of some of the polygenic influences in hypertension may lead to even better treatment protocols to minimize the disease complications of elevated blood pressure.

Topics: Alleles; Angiotensinogen; Blood Pressure; Genetic Linkage; Humans; Hyperaldosteronism; Hypertension; Mutation; Peptidyl-Dipeptidase A

Topics: Angiotensinogen; Animals; Cardiovascular System; Humans; Hypertension; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Blood pressure is a quantitative trait that varies along a continuum in the general population and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Family studies and twin studies suggest that about 30% of blood pressure variance is attributable to genetic factors and 50% to environmental factors. Two forms of hypertension transmitted on an autosomal recessive basis have been identified: one is glucocorticoid-suppressible hyperaldosteronism (GSH) and the other is Liddle's syndrome (amiloride-suppressible hyperactivity of the epithelial sodium channel). The molecular basis for these two forms of severe hypertension has recently been elucidated. GSH is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. Apart from these rare genetic defects, a number of susceptibility genes can increase the risk of hypertension in a given environment. Their presence is neither necessary nor sufficient to cause hypertension. The best documented example is the angiotensinogen gene. Angiotensiongen is the substrate of renin, and the renin-angiotensinogen reaction is the first and limiting step in the pathway that leads to production of angiotensin II, a peptide with important effects on blood pressure control and the metabolism of water and sodium. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension or hypertension of pregnancy. The M235T variant of angiotensinogen is more prevalent among hypertensive than among normotensive subjects in several Caucasian and Japanese populations. The M235T variant is also associated with plasma angiotensinogen elevation, which is potentially responsible for increased production of angiotensin II. In other terms, relationships exist between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distal phenomenon (i.e., blood pressure elevation)

Topics: Angiotensinogen; Female; Humans; Hypertension; Molecular Biology; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Renin-Angiotensin System

Topics: Angiotensin I; Angiotensinogen; Animals; Homeostasis; Humans; Hypertension; Mutation; Tissue Distribution

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Disease Models, Animal; Endothelins; Humans; Hypertension; Peptidyl-Dipeptidase A; Rats; Renin

Topics: Angiotensin II; Angiotensinogen; Animals; Female; Humans; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Pregnancy; Renin-Angiotensin System; Risk Factors; Signal Transduction

Recently, an allelic variant of the angiotensinogen gene (AGT 235T) has been associated with increased risk of hypertension. However, this finding has not been confirmed by all investigators. A meta-analysis was performed to examine the association between the AGT 235T-allele and hypertension in whites and to identify potential reasons for the controversial results. All relevant articles published between 1992 and 1996 were identified through multiple sources. The studies were methodologically appraised, and the frequency of the AGT 235T-allele was extracted. The 235T-allele frequency was pooled using the common odds ratio (OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day test. Together these studies present data on 5493 patients. The AGT 235T-allele was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29; P<.0001). This association increased in studies with positive family history (OR: 1.42; 95% CI: 1.25 to 1.61, P<.0001), recruitment of cases from referral centers (OR: 1.39; 95% CI: 1.20 to 1.62, P<.0001), and more severe hypertension (OR: 1.34; 95% CI: 1.22 to 1.47, P<.0001). However, the presence of methodological problems in all studies gives rise to serious concerns regarding bias and confounding. Despite a statistically significant, albeit weak, association between the AGT 235T variant and hypertension that has been confirmed through sensitivity analysis, this finding has to be interpreted with caution, as the methodological weaknesses of the individual studies are likely to have biased the outcome of the meta-analysis. Clearly, more rigorous methods need to be applied in association studies on the genetics of human hypertension.

Topics: Alleles; Angiotensinogen; Biometry; Databases, Bibliographic; Gene Frequency; Genetic Variation; Humans; Hypertension; MEDLINE; Odds Ratio; Sensitivity and Specificity; White People

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; DNA; Endothelins; Female; Gene Targeting; Genetic Vectors; Hypertension; Male; Mice; Mice, Inbred Strains; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Sequence Homology, Nucleic Acid; Stem Cells

Although it has been recognized for almost 70 years that there is a substantial genetic component to the pathogenesis of hypertension, only recently have systematic efforts been made to identify the responsible genetically determined mechanisms. In the case of several rare syndromes, spectacular progress has been made in identifying the underlying molecular mechanisms responsible for the clinical expression. Glucocorticoid-suppressible aldosteronism and Liddle's syndrome, each inherited as an autosomal-dominant condition, complete the list. In the case of randomly selected patients and families with essential hypertension, inheritance involves many genes and progress has been far more modest. Probably the most promising lead has involved the genes governing the structure of angiotensinogen, the substrate in the renin reaction. Linkage has been established and confirmed. At the moment, however, neither the relation of the genetic abnormality to the underlying mechanisms, nor the contribution of this abnormality to hypertension in the individual patient, has been defined. We know less about other candidate genes, with the exception of studies that rigorously ruled out a contribution. The development of the concept of the "intermediate phenotype," a physiological feature that makes it possible to identify a homogeneous subpopulation, should help to sort out many of these issues. Unfortunately, the identification and characterization of intermediate phenotypes is substantially more difficult at the moment than are the genetic studies, and so progress is likely to be slow. The field is complicated by the reporting of claims made on the basis of small patient samples. In the case of polymorphisms in the angiotensin-converting enzyme gene as a risk factor for tissue injury, for example, substantial follow-up studies have systematically failed to confirm the original report, which was based on a small patient sample. The fact that the same DNA collection is likely to be examined many times for multiple gene candidates creates a setting in which type I errors are likely, and so we are likely to see many more examples. Caveat lector. Again, the development of relevant intermediate phenotypes will make the spurious association less likely.

Topics: Angiotensinogen; Atrial Natriuretic Factor; Genes, Dominant; Humans; Hyperaldosteronism; Hypertension; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Genetic; Racial Groups; Renin-Angiotensin System; Syndrome

The candidacy of angiotensinogen for a role in the genetic basis of hypertension is supported by the observation that plasma angiotensinogen levels track with raised blood pressure through families. In addition, transgenic mice with overexpression of a rat angiotensinogen gene develop hypertension, and knockout mice with a disrupted gene and absent angiotensinogen production develop low blood pressure. There are now two studies in populations of white European origin and one in African Caribbeans providing support for a role of the angiotensinogen gene locus in human essential hypertension.

Topics: Angiotensinogen; Animals; Genetic Linkage; Genetic Variation; Humans; Hypertension

Angiotensinogen is the only known substrate for the enzyme renin. Angiotensin II, the end product of the reaction, is an extremely potent vasoconstrictor and a major determinant of salt and water homeostasis. It is also a growth factor. Angiotensinogen has been identified as a non-inhibitory member of the serine proteinase inhibitor family. Although the most abundant source of plasma angiotensinogen is the liver, the use of Northern blotting and reverse transcriptase PCR techniques has confirmed angiotensinogen mRNA expression in a wide range of tissues, including the kidney, brain, vascular tissue, adrenal gland, placenta and leucocytes. The sequencing of the rat and human angiotensinogen genes has increased our understanding of this protein and its role in physiology and the pathogenesis of human disease. Early observations on the regulation of angiotensinogen are now explicable at the molecular level, with the identification of the core promoter, hormone and acute phase responsive elements and tissue-specific enhancers. The role of angiotensinogen in the aetiology of hypertensive disorders has been tested in transgenic animals, and in case-controlled genetic association and linkage studies. This review examines our current understanding of angiotensinogen, in the light of recent advances.

Topics: Angiotensinogen; Animals; Base Sequence; DNA; Female; Gene Expression; Humans; Hypertension; Molecular Structure; Molecular Weight; Pregnancy; Rats; Renin-Angiotensin System

It is generally accepted that the etiology of essential hypertension is due to a complex interplay of genetic and environmental factors. A great deal of research effort over the past ten years has been focused on the identification of genes the variants of which predispose individuals to high blood pressure. Consequently, transgenic and knockout animals have become important research tools, providing experimental systems in which defined genetic manipulations can be introduced on uniform genetic backgrounds while minimizing environmental variation. These animal models have provided the means by which candidate genes thought to be involved in blood pressure regulation have been studied. Furthermore, these models can be used to test the significance of genes and gene variants identified via genome-wide searches as potential causes of hypertension. The purpose of this review is to provide a brief discussion of transgenic and knockout methodology and its application to study the genetic basis of hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Gene Expression; Gene Expression Regulation; Hypertension; Mice; Mice, Transgenic

Angiotensin-converting enzyme inhibitors have proven to be uniquely effective in inducing regression, or preventing the occurrence, of ventricular hypertrophy associated with systemic hypertension. This has pointed, for many years, to a possible direct involvement of the renin-angiotensin system in the pathogenesis of cardiac hypertrophy. Over the last 10 years further supporting evidence has been forthcoming about direct trophic effects of angiotensin II in several experimental systems. Additionally, we now have rather conclusive evidence for the existence of a local, intracardiac renin-angiotensin system, which is capable of synthesis of all components of the system, and of cleaving, via the classic pathway, angiotensin peptides from the precursor, angiotensinogen. Moreover, a number of studies have demonstrated the capacity of regulatory response and modulation of activity of the local system in response to a variety of pharmacologic perturbations as well as differential expression of specific components under pathologic conditions, including compensatory hypertrophy and remodeling after myocardial infarction, pressure overload hypertrophy, and volume overload hypertrophy. Continued research into the role of the cardiac renin-angiotensin system in the pathogenesis of cardiac hypertrophy and failure will provide us with the tools to devise more specific, targeted strategies for therapeutic intervention or prevention.

Topics: Adaptation, Physiological; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cardiomegaly; Humans; Hypertension; Myocardial Infarction; Myocardium; Renin-Angiotensin System

In the past few years, a number of key insights have been made concerning the genetic basis of hypertension and blood pressure regulation. The genes responsible for two Mendelian forms of hypertension, glucocorticoid-remediable aldosteronism and Liddle's syndrome, were identified. In addition, research into the role of the renin-angiotensin system in blood pressure regulation has further implicated the angiotensinogen and angiotensin-converting enzyme loci in hypertension and its complications, such as myocardial infarction. Finally, several new candidate genes for hypertension have been identified through the use of genome scanning and contemporary gene expression assays in model organisms.

Topics: Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Gene Expression; Genetic Linkage; Genetic Variation; Genome; Glucocorticoids; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Mice; Mice, Transgenic; Peptidyl-Dipeptidase A; Rats; Receptors, Angiotensin; Syndrome

Topics: Angiotensinogen; Animals; Disease Models, Animal; Genes; Humans; Hypertension; Neuropeptide Y; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin; Type C Phospholipases

On the basis of recent advances in molecular biology and statistical genetics, it has become possible to search for chromosome regions that contain genes predisposing to hypertension and to directly link specific mutations on candidate genes to hypertension. As the human genome has been extensively mapped, highly informative, polymorphic markers are available, which can be used to detect genes in their proximity with 'hypertensinogenic' alleles. Some of these markers have been shown to be tightly linked to the genes of the renin-angiotensin system. Furthermore, the coding and regulatory regions of the genes encoding for renin, ACE, angiotensinogen and the AT1 receptor have been partially characterized. This provides a basis for further definition of specific polymorphisms within these genes that are of functional importance and that can be used to examine their contribution to the inheritance of primary hypertension. The first studies of these links have already emerged and have been reviewed in this article. Several problems arise in performing such linkage studies in human primary hypertension, however. It is difficult to define the genetic background of heterogeneous, multigenetic and multifactorial diseases such as human hypertension. Extensive studies of population genetics, including the analysis of large numbers of generations and controlled breeding experiments, cannot be performed, for obvious reasons. Blood pressure is not a convenient study trait, because it exhibits great intraindividual variance and also because of the relatively low reliability of just a few indirect measurements obtained under loosely controlled environmental conditions. Twenty-four-hour ambulatory blood pressure measurements may improve such investigations in the near future. Ravogli et al (1990) reported that the 24-hour ambulatory systolic blood pressure is higher in normotensive subjects of hypertensive parents than in normotensive subjects of normotensive parents--a finding that had not been previously reported using the conventional method of measurement. Hypertension as a trait per se is also problematic: its classification (above 140/90 mmHg) is purely artefactual, and its aetiology is highly heterogeneous. Thus, we have to keep in mind that even strong gene effects, if present in only a small subgroup of hypertensives, may not be detected in these studies. Attempts are being made to strengthen the analysis by characterizing physiologically distinct subgroups. In ad

Topics: Angiotensin II; Angiotensinogen; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Infarction; Peptidyl-Dipeptidase A; Pre-Eclampsia; Pregnancy; Receptors, Angiotensin; Renin; Renin-Angiotensin System

The renin-angiotensin system (RAS) plays a key role in the regulation of the circulation and is critically involved in the pathogenesis of several diseases, including hypertension. Renin is synthesized mainly in the kidney and is secreted into the bloodstream. It catalyzes the rate-limiting cleavage of substrate angiotensinogen, which is derived mainly from the liver, to generate angiotensin I. Renin and angiotensinogen genes have been isolated and their structure has been determined by the methods of molecular biology. Renin and angiotensinogen genes are expressed in many tissues, and the tissue-specific regulation of these genes has been studied. The existence of local RASs in contrast to the classical circulating RAS has been suggested, although their exact functional role remains to be determined. Recent molecular analyses have led to a detailed description of the transcriptional mechanism of the renin and angiotensinogen genes, and have made it possible to study the regulation of the expression of these genes in several physiological and pathological states. In addition, several types of transgenic animals have been developed to study the functional importance of the RAS in vivo. Transgenic mice with human renin and human angiotensinogen genes may be a good model of human hypertension. In such mice, the human genes are expressed in the normal tissue-specific pattern, the circulating RAS is activated, and blood pressure is high. Finally, angiotensinogen-deficient mice have also been developed by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen in the liver. As a result, they have no plasma immunoreactive angiotensin I and are hypotensive. The profound hypotension in these mice indicates the importance of the RAS in maintaining pressure.

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Gene Expression Regulation; Humans; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Renin; Renin-Angiotensin System

Topics: Angiotensinogen; Animals; Antigens, CD; Chromosome Mapping; Disease Models, Animal; Female; Humans; Hypertension; Leukosialin; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Repetitive Sequences, Nucleic Acid; Sialoglycoproteins

Topics: Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Molecular Biology; Peptidyl-Dipeptidase A; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Renin; Renin-Angiotensin System

The renin-angiotensin system is intimately involved in the control of sodium and water balance, the activity of the sympathetic nervous system, mitogenesis and the regulation of vascular tone. There is evidence that many of these effects may be controlled at a local level by independent tissue renin-angiotensin systems. Drugs that are specific inhibitors of the cascade have proved powerful tools for dissecting the physiology of the renin-angiotensin system, and are of major benefit in the treatment of hypertension and chronic heart failure. Recent evidence suggests that variations in the genes coding for components of the system may affect the risk of developing hypertension and ischaemic heart disease.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Cardiovascular Diseases; Humans; Hypertension; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System; Sympathetic Nervous System; Vascular Resistance; Vasoconstriction

Topics: Angiotensinogen; Humans; Hypertension

Although essential hypertension has long been recognized to involve a strong genetic predisposition, the genes that increase susceptibility remain virtually unknown. With recent advances in molecular biology and statistical methods, it has become feasible to study candidate genes which may contribute to the pathogenesis of essential hypertension in humans. Recently, the angiotensinogen (AGT) locus was demonstrated to exhibit genetic linkage and association to essential hypertension and to preeclampsia. While the statistical evidence that mutations of the AGT gene or a neighboring gene contribute to the development of hypertension is strong, the exact mechanism(s) by which these mutations affect the regulation of blood pressure (BP) is unknown. Increasing attention is now being focused on elucidating this mechanism(s).

Topics: Amino Acid Sequence; Angiotensinogen; Angiotensins; Blood Pressure; Humans; Hypertension; Molecular Sequence Data; Renin-Angiotensin System

New technologies in molecular biology and medicine have opened new avenues for the study of disease. As a result of this, the genetic basis of many diseases has been discovered and candidate genes that contribute to the underlying pathology have been identified. An important approach to test the function of these genes is the establishment of transgenic animal models. Candidate genes can be expressed in these animals to study their regulation in vivo. Furthermore, the pathophysiological consequences of the alteration in gene expression can be investigated in detail. Like many other diseases, primary hypertension is influenced by genetic factors. A number of candidate genes have been implicated in its pathogenesis, and current research efforts are directed toward testing these candidates. For this purpose, several transgenic animal models have been established. Most of this transgenic work has been carried out in mice, but recent efforts have focused on the development of transgenic rat models for hypertension, which may provide the better experimental system for the study of cardiovascular regulation.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Disease Models, Animal; Gene Expression Regulation; Humans; Hypertension; Mice; Mice, Transgenic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System

Recent advances in the genetics of hypertension include studies on localizations of many loci involved in blood pressure regulation in the rat, elucidation of the molecular mechanisms underlying monogenetic forms of hypertension, and studies of candidate genes in primary hypertension. Evidence that the angiotensinogen gene is involved in primary hypertension has been found by linkage in affected sibling pairs, and by the demonstration of increased risk of disease associated with DNA variants of the gene. Similar evidence of linkage and association has been found in preeclampsia, which suggests that the two diseases share at least one common factor of genetic susceptibility.

Topics: Angiotensinogen; Animals; Genetic Diseases, Inborn; Humans; Hypertension

Variance of blood pressure in the normal population is composed of environmental influences and the cumulative effects of gene structure polymorphisms. Essential hypertension results from the combined influence of these components, whose respective importance can vary considerably from individual to individual. In the rare forms of hypertension due to a single gene abnormality, the environmental component is negligible and the genetic component is represented by a major transmitted gene abnormality with major effects on the phenotype. These rare forms of monogenic hypertension offer interesting models for the study of the genes involved in essential hypertension. The angiotensinogen gene represents the first example of a strongly supported implication of a gene in essential hypertension. The success of this strategy allows the possibility of identifying other genes in essential hypertension.

Topics: Angiotensinogen; Animals; Cloning, Molecular; Genes; Genetic Linkage; Genetic Markers; Genotype; Humans; Hypertension; Phenotype; Rats

Hypertension shares several characteristics with diabetes, atherosclerosis and asthma. These common diseases are caused by environmental factors and predisposing genes and they represent a major cost in developed countries. Use of molecular techniques: Much information is expected from the identification of the molecular bases of these diseases, and from the molecular characterization of the predisposing variants and their effects on the clinical manifestations of these pathologies. Hypertension is now a target for genetic studies, and some interesting results have been obtained in humans and in animal models.

Topics: Angiotensinogen; Animals; Cloning, Molecular; Disease Models, Animal; Female; Genetic Markers; Genetic Variation; Humans; Hypertension; Male; Molecular Biology; Rats; Risk Factors

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Humans; Hypertension; Male; Mice; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System

Topics: Amino Acid Sequence; Angiotensinogen; Animals; Cardiomegaly; Humans; Hypertension; Molecular Probes; Molecular Sequence Data; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Signal Transduction; Vascular Diseases

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Humans; Hypertension; Male; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System

The generation of genetically modified animals by transgenic technology has proven to be a surprisingly versatile resource for researchers, providing an increasing number of new tools for biological investigation. As well as permitting the analysis of gene function and regulation in vivo, modifications of the techniques are being used to suppress or abolish the expression of specific genes, and further refinements have permitted the ablation of specific cell-types and the development of differentiated cell lines from tissue-specific tumours. In hypertension research, where many important questions have been frustratingly difficult to address by previously available methods, the advances afforded by transgenic studies have already been significant and are likely to be even more profound in the future. With the further development of these techniques, it may be possible to produce new and more representative models of essential hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Gene Expression Regulation; Hypertension; Models, Genetic; Renin

Topics: Amino Acid Sequence; Angiotensinogen; Animals; Blood Pressure; Cloning, Molecular; DNA; Gene Expression Regulation; Humans; Hypertension; Membrane Proteins; Mice; Mice, Transgenic; Molecular Sequence Data; Potassium Channels; Potassium Channels, Voltage-Gated; Receptors, Cell Surface; Receptors, Endothelin; Receptors, Neurokinin-1; Receptors, Neurotransmitter; Renin; RNA, Messenger

Topics: Angiotensinogen; Animals; Chromosome Mapping; Genetic Markers; Humans; Hypertension; Kallikreins; Major Histocompatibility Complex; Rats; Rats, Inbred Strains; Renin

Because of its small size, low cost of maintenance, breeding capabilities in captivity, the marmoset, a New World monkey, appears well suited for clinical and fundamental investigations. The contribution of this laboratory animal in the main areas of biomedical research is succinctly described: viral oncology, infections diseases, immunology, reproduction, toxicology and teratology, odontology, behaviour and neuro-psychopathology. Emphasis is put upon the exceptional interest of the use of marmoset as a biological model in cardiovascular studies.

Topics: Angiotensinogen; Animals; Arteriosclerosis; Callitrichinae; Cardiovascular Diseases; Disease Models, Animal; Hypertension; Research

Several immunologic approaches to blockade of the renin-angiotensin system (RAS) have been reported, involving most of the proteins and peptides of the biochemical cascade: renin, substrate, angiotensins, and converting enzyme. None as yet has involved blockade of angiotensin II receptors. Earlier and more recent studies used passive transfer of heterologous antibodies or active immunization against RAS proteins and peptides. Passive transfers have been performed with both polyclonal antibodies and now with specific monoclonal immunoglobulins. The latter are better defined in affinity, quantity, and capacity to bind and thus inhibit the biologic activity of the antigen. Active immunization produced long-term blockade of part or all of the biologic activity of the system. The immunopathologic consequences of the use of antibodies raised against a self-antigen could be of interest in defining the predominant site of storage and secretion of the relevant protein and hence the respective roles of different tissues in the production of specific proteins in, for example, the vascular pulmonary bed for converting enzyme and renal arterial tree for renin. In all cases immunologic methods offer in vivo experimental models of short- or long-term RAS blockade that could be compared with pharmacologic methods, such as converting-enzyme inhibition, angiotensin II antagonists, and renin inhibitors.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Humans; Hypertension; Immunization, Passive; Immunotherapy; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

The existence of a brain renin-angiotensin system (RAS) as one of various tissue RASs is now firmly established. Angiotensin-containing pathways within brain areas involved in central blood pressure regulation have been described. Evidence from biochemical, neurophysiologic, pharmacologic, and most recently, molecular genetic studies indicate that the brain RAS is regulated independently of the hormonal RAS and may contribute to blood pressure control and body fluid homeostasis. In addition, circulating angiotensin II can exert some of its action through stimulation of brain angiotensin receptors accessible from the blood. In experimental animal preparations of hypertension, especially in spontaneously hypertensive rats, an overactive brain RAS may be one of the factors involved in pathogenesis and maintenance of hypertension. In spontaneously hypertensive rats, inhibitors of the angiotensin II-generating converting enzyme (CE) have been shown to lower blood pressure by a central action when applied to the brain and to inhibit brain CE when applied systemically. The pathogenetic mechanisms underlying a particular cardiovascular disease and the characteristics of the CE inhibitor used (e.g., its lipid solubility governing penetration into tissue) may determine the degree to which CE inhibition within a given organ, such as the brain, contributes to the action of these drugs.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Brain; Hypertension; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Topics: Aldosterone; Angiotensinogen; Catecholamines; Creatinine; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Posture; Renin

Topics: Amino Acid Sequence; Angiotensinogen; Apoproteins; Arteriosclerosis; Atrial Natriuretic Factor; Cloning, Molecular; DNA; Genetic Engineering; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type III; Hypertension; Myosins; Receptors, Cell Surface; Receptors, Lipoprotein; Sodium-Potassium-Exchanging ATPase

Topics: Angiotensinogen; Blood Pressure; Female; Fetal Blood; Humans; Hypertension; Labor, Obstetric; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Renin-Angiotensin System

Topics: Angiotensin II; Angiotensinogen; Animals; Arginine Vasopressin; Blood Pressure; Brain; Brain Mapping; Cardiovascular Physiological Phenomena; Cardiovascular System; Cattle; Desoxycorticosterone; Dogs; Humans; Hypertension; Hypothalamo-Hypophyseal System; Mice; Neurotransmitter Agents; Oxytocin; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sodium Chloride; Subfornical Organ

Angiotensin II, the biologically active component of the renin-angiotensin system, acts throughout the body to produce an impressive number of cardiovascular, endocrine, metabolic, and behavioral effects. Major actions include elevation of arterial pressure, stimulation of aldosterone secretion, and a variety of effects on the kidneys, brain, and pituitary. Investigation of the role of the renin-angiotensin system in physiological regulation has been greatly facilitated by the availability of specific inhibitors of the formation or actions of angiotensin II, most notably converting-enzyme inhibitors and angiotensin receptor antagonists. Studies with these agents have clearly shown that the renin-angiotensin system plays an important role in the defense of body balance and blood pressure in hypovolemic state, including sodium deficiency and hemorrhage. The inhibitors also lower blood pressure in some forms of hypertension, and converting-enzyme inhibitors are proving to be effective antihypertensive agents.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Brain; Hemorrhage; Humans; Hypertension; Kidney; Peptidyl-Dipeptidase A; Pituitary Gland; Renin; Renin-Angiotensin System; Water-Electrolyte Balance

Although renin was identified as playing a part in cardiovascular homeostasis by the experiments of Goldblatt in the 1930s, neither its physiological role in organs other than the kidney nor its contribution to the genesis of essential hypertension have been defined. It is difficult to interpret studies with converting enzyme inhibitors because of their multiple pharmacological effects. Specific inhibitors of renin appropriate for clinical investigation would help to resolve many questions. Four classes of compounds have been shown to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogues of angiotensinogens and peptides that are related to the amino-terminal sequence of prorenin. Of these, it is likely that angiotensinogen analogues will be the first applied in human studies. The minimal substrate for renin has the sequence: His-Pro-Phe-His-Leu-Val-Tyr. Variants of this sequence have yielded competitive inhibitors. Remarkably active compounds have recently been synthesized by reducing the peptide bond that is cleaved by renin, or by incorporating the amino acid statine, found in pepstatin. These compounds have been shown to be effective in dogs, rats and monkeys and, most recently, preliminary studies have reported their efficacy in man. Recent studies with one of these inhibitors, RIP, raise questions concerning both its specificity and site of action.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antibodies, Monoclonal; Antihypertensive Agents; Blood Pressure; Heart Rate; Humans; Hypertension; Oligopeptides; Pepstatins; Renin

Topics: Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cloning, Molecular; DNA; Genes; Humans; Hypertension; Kallikreins; Kininogens; Kinins; Renin; Renin-Angiotensin System; RNA, Messenger

The review will cover the chemistry and biochemistry of angiotensin-converting enzyme inhibitors with emphasis on data published since the publication of previous reviews. The relative merits of each contribution will be evaluated, as well as their potential for leading to new discoveries. The biology of angiotensin-converting enzyme inhibitors will be brought up-to-date to give the reader an appreciation of the medical implications of this new type of antihypertensive agent.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Disease Models, Animal; Heart Failure; Humans; Hypertension; Kidney; Oligopeptides; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Structure-Activity Relationship; Substrate Specificity

The renin-angiotensin system is an important regulator of vascular resistance in many patients with hypertension and congestive heart failure. To quantitatively evaluate this contribution requires correlation of markers of the renin-angiotensin system with haemodynamic parameters, notably blood pressure, cardiac output, and calculated systemic vascular resistance. In addition, to determine ventricular loading properties, assessment of cardiac filling pressures is also required. The availability of specific pharmacological inhibitors of the renin-angiotensin system greatly enhances such correlation, as the haemodynamic consequence of blocking the renin-angiotensin system can then more fully identify its contribution. In the last decade, highly specific pharmacological inhibitors have become available to serve such a purpose. Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin. However, this method of blockade is still at the early stages of investigation. More readily available are converting enzyme inhibitors which block the formation of angiotensin II, the potent vasoconstrictor which mediates increased systemic vascular resistance, and angiotensin II analogues which compete with endogenous angiotensin II for vascular and adrenal receptors. Although hypertension and chronic congestive heart failure are clinically distinct entities in many respects, their common bond is the fact that both pathological mechanisms are mediated by an increase of systemic vascular resistance. The implications of blocking the resulting vasoconstriction in both entities are therefore quite similar. This review summarises our present knowledge of the contribution of the renin-angiotensin system to the vasoconstriction of hypertension and congestive heart failure, and also summarises the haemodynamic consequences of such inhibition. The implications of the response to these specific pharmacological probes, as well as their limitations, are discussed. Their importance rests not only in their therapeutic application, but also in their contribution as probes for pathophysiological mechanisms of vasoconstriction in cardiovascular disease.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Dipeptides; Enalapril; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Kinetics; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin; Renin-Angiotensin System; Teprotide

Discussed in this article are the effects of pregnancy-induced hypertension on the renin-angiotensin-aldosterone system; the possible role of prostanoids, deoxycorticosterone, and deoxycorticosterone sulfate in blood pressure control; and the effect of pregnancy-induced hypertension upon the endocrinology of the maternal-fetal-placental unit.

Topics: Adolescent; Adrenocorticotropic Hormone; Angiotensin II; Angiotensinogen; Animals; Estrogens; Female; Humans; Hypertension; Maternal-Fetal Exchange; Peptidyl-Dipeptidase A; Pregnancy; Pregnancy Complications, Cardiovascular; Progesterone; Prolactin; Prostaglandins; Renin; Renin-Angiotensin System

Topics: Angiotensin I; Angiotensin II; Angiotensin III; Angiotensinogen; Animals; Humans; Hypertension; Kidney; Oligopeptides; Pepstatins; Renin; Renin-Angiotensin System; Teprotide

Topics: Amniotic Fluid; Angiotensin II; Angiotensinogen; Endopeptidases; Female; Fetal Blood; Fetus; Humans; Hypertension; Juxtaglomerular Apparatus; Postpartum Period; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins E; Renin; Renin-Angiotensin System

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocorticotropic Hormone; Angiotensinogen; Body Fluids; Captopril; Cushing Syndrome; Glucocorticoids; Humans; Hypertension; Pituitary Gland; Potassium; Renin-Angiotensin System; Saralasin; Sodium; Tomography, X-Ray Computed

Topics: Adrenergic beta-Antagonists; Adult; Aldosterone; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Malignant; Hypertension, Renovascular; Kidney Failure, Chronic; Male; Molecular Weight; Peptidyl-Dipeptidase A; Radioimmunoassay; Renin

Topics: Aldosterone; Angiotensinogen; Desoxycorticosterone; Diet, Sodium-Restricted; Diuretics; Female; Humans; Hydrocortisone; Hypertension; Mineralocorticoids; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Sodium

Topics: Angiotensinogen; Angiotensins; Animals; Enzyme Activation; Humans; Hypertension; Molecular Weight; Rats; Renin

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.

Topics: Aldosterone; Angiotensin II; Angiotensin III; Angiotensinogen; Animals; Cattle; Dogs; Endopeptidases; Humans; Hypertension; Peptidyl-Dipeptidase A; Rabbits; Rats; Renin; Swine

Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis.. In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring.. Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.. Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).

Topics: Angiotensinogen; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diet; Double-Blind Method; Humans; Hypertension; Injections, Subcutaneous; Irbesartan; RNA Interference; Tetrazoles

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Topics: Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Outcome

The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for essential hypertension. The aim of this study was to examine the association between the A-6G variant of the AGT gene and the blood pressure response to angiotensin-converting enzyme (ACE) inhibitors in hypertensive subjects.. Five hundred and nine mildly to moderately hypertensive subjects received ACE inhibitors for six weeks after a two-week run-in period. AGT genotyping was performed by direct polymerase chain reaction amplification and deoxyribonucleic acid (DNA) nucleotide sequencing from peripheral blood.. The AA genotype, AG genotype, and GG genotype were present in 301 (59.1%), 186 (36.6%), and 22 (4.3%) of patients, respectively. As compared with patients carrying the AA or AG genotype, those carrying the GG genotype had significantly greater reductions in systolic blood pressure, diastolic blood pressure, pulse pressure and mean arterial pressure (p=0.007, 0.014, 0.027 and 0.005, respectively). Moreover, stepwise multiple linear regression analysis showed that the A-6G genotype was a significant predictor of systolic blood pressure and pulse pressure reductions (p=0.040 and 0.019, respectively).. Our study indicates that the A-6G variant of the AGT gene may be an important determinant of interindividual variation in the response to ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Diastole; Essential Hypertension; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Promoter Regions, Genetic; Systole

It has been suggested that genetic backgrounds, which have an association with essential hypertension, may also determine the responsiveness to ACE inhibitor. We determined the association of angiotensinogen (M235T) gene polymorphism with essential hypertension and the relationship between polymorphism in the angiotensinogen (M235T) gene and blood pressure response to ACE inhibitor (Enalapril) in patients with essential hypertension from northern Indian subjects.. 250 patients with essential hypertension and 250 normal healthy controls from Delhi and surrounding areas were recruited for the investigation. Blood pressure was recorded before and after 6 weeks of treatment with ACE inhibitors, Enalapril. Genotyping were carried out by polymerase chain reaction and Restriction fragment length polymorphism technique.. Statistically significant association of T allele was observed with essential hypertension [x2 = 14.67, p = 0.00013, Odds ratio = 1.76 (1.3-2.32) at 95% CI], the relative risk at 95% CI being 1.28 (1.2-1.54). The decrease in systolic blood pressure and diastolic blood pressure after six weeks of treatment of the patients carrying TT genotype (SBP = 26 ± 17.4 mmHg, DBP = 14.83 ± 7.6 mmHg) were greater than the groups carrying MT (SBP = 3.0 ± 7.8 mmHg, DBP = 6.2 ± 3.0 mmHg) and MM genotypes (SBP = 1.2 ± 0.8 mmHg, DBP = 0.10 ± 12.1 mm Hg.. The angiotensinogen (M235T) gene polymorphism is significantly associated with essential hypertension. Patients carrying TT genotype had higher blood pressure lowering response when treated with ACE inhibitor, Enalapril than those carrying MM and MT genotypes suggesting that the T allele may be a possible genetic marker for essential hypertension.

Topics: Adult; Alleles; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Enalapril; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; White People

Essential hypertension results from the interaction of several genetic and environmental factors. Identification of genetic factors that modulate blood pressure (BP) response to interventions can lead to improved strategies for prevention and control. The purpose of this study was to identify genes that modulate BP response to dietary interventions.. We used data and samples collected in two randomized feeding studies to determine the extent to which genetic architecture is associated with the effect on BP of sodium intake and the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. Participants in both trials were adults with above-optimal BP or unmedicated stage 1 hypertension. Genomic DNA was typed for several candidate genes.. The effect of sodium intake on BP differed by genotype at the angiotensinogen, β2-adrenergic receptor, and kallikrein loci. The effect of DASH dietary pattern on BP differed by genotype at the β2-adrenergic receptor locus.. These findings have implications for understanding the mechanism(s) through which diet affects BP, the heterogeneity of these effects, and the extent to which dietary interventions can modulate genetic predisposition.

Topics: Adrenergic Fibers; Adult; Angiotensinogen; Blood Pressure; Diet, Sodium-Restricted; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Kallikreins; Linkage Disequilibrium; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2; Renin-Angiotensin System; Risk Assessment; Risk Factors; Sodium, Dietary; Sympathetic Nervous System; Treatment Outcome

Conjugated linoleic acid (CLA) refers to a group of positional and geometrical conjugated dienoic isomers of linoleic acid. Our aim was to investigate the effect of 8-week dietary CLA supplementation on blood pressure, concentrations of plasma adiponecin, leptin, and as well as angiotensin-converting enzyme (ACE) activity in obese hypertensive subjects.. Eighty obese individuals with stage 1 uncontrolled essential hypertension were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 4.5 g/day CLA (nine 0.5-g capsules; a 50:50 isomer blend of c 9,t 11 and t 10,c 12 CLA) with 37.5 mg/day ramipril (group 1) or placebo with 37.5 mg/day ramipril (group 2) for 8 weeks. Baseline and endpoint systolic BP, diastolic BP, and concentrations of plasma adiponecin, leptin, angiotensinogen, and ACE activity were measured.. Treatment with CLA significantly enhanced the reduction effect of ramipril on systolic BP and diastolic BP (P < 0.05). It also increased plasma adiponectin concentration (P < 0.05) and decreased plasma concentrations of leptin and angiotensinogen (P < 0.05); however, significant change was not observed in ACE activity.. An 8-week long supplementation of CLA enhanced the effect of ramipril on blood pressure reduction in treated obese hypertensive patients. The antihypertensive effect of CLA might be related to the changed secretion of hypertensive adipocytokines in plasma.

Topics: Adiponectin; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Female; Follow-Up Studies; Humans; Hypertension; Leptin; Linoleic Acids, Conjugated; Male; Middle Aged; Obesity; Ramipril; Treatment Outcome

Research suggests pulse pressure (PP) is a predictor of cardiovascular disease, and genes likely influence PP levels. Additionally, gender may be an effect modifier between PP and cardiovascular disease. This study addresses whether two renin-angiotensin-aldosterone system (RAAS) variants are associated with PP in a sex-specific manner (genotype-by-sex interaction). Subjects comprised 35,048 GenHAT study participants over 55 years old, approximately half were women and half non-Hispanic white. Blood pressure measurements were obtained 6 months after randomization to one of four antihypertensive medications. The polymorphisms considered were AGT-6 and ACE-I/D. We employed linear regression to assess the interaction. AGT-6 showed a significant (p < 0.001) genotype-by-sex interaction. Men with the 'G/G' genotype had a higher PP (0.6 mm HG) than men carrying an 'A' allele, while 'G/G' women had a lower PP (0.7 mm Hg) than women carrying an 'A' allele. Three of the four treatment groups (chlorthalidone, amlodipine and lisinopril) suggested a consistent interaction in sub-group analyses (only amlodipine was statistically significant, p < 0.001), whereas doxazosin did not. The interaction was evident among non-Hispanic participants but not among Hispanic participants. For ACE-I/D no evidence for a genotype-by-sex interaction was detected. This finding of genotype-by-sex interaction on PP helps our understanding of the complexity of genetic effects on blood pressure.

Topics: Aged; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Sequence Deletion; Sex Characteristics

This study examined the association between T1198C polymorphism of the angiotensinogen (AGT) gene and the blood pressure response to ACE inhibitors in a Chinese hypertensive cohort. After a 2-week single-blind placebo run-in period, benazepril (10-20 mg/day) or imidapril (5-10 mg/day) was administered for 6 weeks to 509 patients with mild-to-moderate essential hypertension. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the polymorphism, and the patients were classified as having the TT, TC, or CC genotype. The achieved changes in systolic and diastolic blood pressure (SBP and DBP) were analyzed to determine their association with genotypes at the AGT gene locus. In the total 509 patients, the TT genotype was observed in 44 patients (8.7%), the TC genotype in 214 patients (42.0%), and the CC genotype in 251 patients (49.3%). The SBP reductions in patients with the TT genotype, TC genotype, and CC genotype were -15.3+/-12.7 mmHg, -14.0+/-12.7 mmHg, and -14.4+/-12.4 mmHg, respectively (p=0.809). The DBP reductions in patients with the TT genotype, TC genotype, and CC genotype were -8.5+/-8.1 mmHg, -8.3+/-7.5 mmHg, and -8.9+/-6.6 mmHg, respectively (p=0.638). There were no significant differences in the changes in SBP or DBP after treatment among the three genotype groups. In conclusion, these results suggest that the AGT genotype does not predict the blood pressure-lowering response to antihypertensive treatment with ACE inhibitors in Chinese hypertensive patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Benzazepines; Blood Pressure; China; Double-Blind Method; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Polymorphism, Genetic

The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment.. Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment.. The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM).. We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Antihypertensive Agents; Atenolol; Biphenyl Compounds; Blood Pressure; Double-Blind Method; Female; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Irbesartan; Male; Middle Aged; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

Hypertension in pregnancy (HP) is a multifactorial disease manifested due to a complex combination of environmental factors and several predisposing genes including factors in the renin angiotensin system. The aim of this study was to assess the association between the A1166C variant of the angiotensin II type 1 receptor (AT1) gene and severe HP. We carried out association studies and multivariate analyses including other candidate causal factors of HP such as the M235T variant of the angiotensinogen (AGT) gene, prepregnancy body mass index (BMI), and family history of hypertension in Japanese subjects. One hundred and fourteen patients with severe HP and 291 normal pregnancy controls were genotyped. Among primiparous subjects, the frequency of "AC+CC genotype of AT1" was significantly higher in severe HP than in the controls. A multivariate analysis with "AC+CC genotype of AT1" and "TT genotype of AGT" revealed that these were independently associated with primiparous severe HP. However, when "family history of hypertension" and "prepregnancy BMI > or =25" were added as factors examined in the multivariate analysis, only "TT genotype of AGT" and "family history of hypertension" were found to be independent potent factors. The present results suggest that the C1166 allele of the AT1 gene may be concerned with the predisposition to essential hypertension independently of the T235 allele of the AGT gene.

Topics: Angiotensinogen; Body Mass Index; Case-Control Studies; Female; Genotype; Humans; Hypertension; Japan; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular; Receptor, Angiotensin, Type 1

Defining the genetic basis of essential hypertension is most informative when the blood pressure regulation is correlated with physiologic mechanisms, e.g., responses of the renin-angiotensin aldosterone system (RAAS) in hypertensive subjects. The aldosterone response to angiotensin II (Ang II) on a low salt diet is influenced by gender, plasma renin activity, and most significantly, familial resemblance, but only in males and in post-menopausal females. There is familial aggregation of low-renin hypertension, no association with candidate genes of the RAAS, but, a highly significant association with polymorphisms in the alpha-adducin gene. Finally, angiotensinogen (AGT) genotype effects renal and adrenal responses to Ang II in patients with hypertension. These results strongly suggest that in contrast to population-based studies that use hypertension as the phenotype, classifying patients by the variability in physiologic, mechanistic traits enhances the probability of identifying the genetic factors influencing a rise in blood pressure.

Topics: Age Factors; Aldosterone; Angiotensin II; Angiotensinogen; Blood Volume; Calmodulin-Binding Proteins; Diet, Sodium-Restricted; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Phenotype; Predictive Value of Tests; Renin; Renin-Angiotensin System; Sex Factors; Vasoconstrictor Agents

Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control.. Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis.. The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction.. SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Antihypertensive Agents; Apolipoproteins B; Atenolol; Biphenyl Compounds; Blood Pressure; Double-Blind Method; Echocardiography; Female; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Irbesartan; Male; Middle Aged; Multivariate Analysis; Oligonucleotide Array Sequence Analysis; Pharmacogenetics; Polymorphism, Single Nucleotide; Predictive Value of Tests; Receptors, Adrenergic, beta-2; Tetrazoles

The angiotensinogen M235T polymorphism has been linked to hypertension and cardiovascular disease. Carotid intima-media thickness (IMT) is an early marker of atherosclerosis. The objectives of the present study were to determine in previously untreated essential hypertensive patients whether carotid IMT was associated with the M235T polymorphism, and to determine whether the M235T polymorphism could influence the reduction of carotid IMT by antihypertensive treatment. Common carotid artery IMT was determined with a high-definition echotracking system in 98 previously untreated hypertensive patients in a cross-sectional study. A subgroup of 56 patients was included in a randomized double-blind parallel group study comparing the effect of the angiotensin-converting-enzyme-inhibitor enalapril with that of the beta-blocker celiprolol during a 5 month period. In the cross-sectional study, a multivariate analysis showed that the M235T genotype was a significant independent determinant of carotid IMT, explaining 7% of the variance. Carotid IMT was higher in patients homozygous for the T allele than in MM patients. In the longitudinal study, the reduction in carotid IMT after antihypertensive treatment was significantly ( P <0.01) higher in patients carrying the TT genotype than in patients carrying the MM genotype, despite similar reductions in blood pressure and independently of drug type. In conclusion, these data suggest that the angiotensinogen TT genotype at position 235 is a genetic marker for early carotid atherosclerosis in a hypertensive population and its regression under antihypertensive treatment.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Angiotensinogen; Antihypertensive Agents; Carotid Artery Diseases; Celiprolol; Cross-Sectional Studies; Echocardiography; Enalapril; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Polymorphism, Genetic; Tunica Intima

Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment.. Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol.. The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

Topics: Aged; Alleles; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Atenolol; Biphenyl Compounds; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Irbesartan; Male; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Sweden; Tetrazoles

Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen (AGT) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies.. Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng x kg(-1) x min(-1)) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular (P=0.0002) and adrenal (P=0.002) responses to infused exogenous Ang II were associated with the AGT -6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT -6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT -6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT -6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the -6AA genotype was present in only 17.8% (P=0.001).. A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT -6A genotype results in increased tissue expression of angiotensinogen and Ang II.

Topics: Adolescent; Adrenal Glands; Adult; Aged; Aldosterone; Angiotensin II; Angiotensinogen; Antihypertensive Agents; Female; Genotype; Humans; Hypertension; Kidney; Male; Middle Aged; Models, Biological; Renal Plasma Flow

The angiotensinogen M235T polymorphism is positively associated with plasma angiotensinogen, hypertension, and coronary heart disease. However, the association of M235T polymorphism with left ventricular (LV) mass and function is not well defined at the population level. We investigated whether 2 tightly linked polymorphisms of angiotensinogen gene, M235T and G-6A, are associated with LV mass and function in a large population-based sample, composed mostly of patients with hypertension.. Two-dimensional guided M-mode and pulsed Doppler scan echocardiograms were performed in 605 participants. The angiotensinogen M235T was analyzed with a standard polymerase chain reaction test, and the G-6A variant was measured with mass spectrophotometry.. The association of angiotensinogen gene to LV mass and LV mass indexed to body surface area (LVMI) differed significantly between subjects with normotensive and hypertensive conditions with respect to the direction of association (P <.005). The methionine-threonine/threonine-threonine genotype was negatively associated with LV mass and LVMI in patients with hypertension after adjustment for blood pressure, antihypertensive medication use, weight, and other covariates (P <.001), and patients with normotensive conditions with the methionine-threonine/threonine-threonine genotype had higher LV mass and LVMI (P =.04, for LV mass; P =.14, for LVMI). The association in patients with normotensive conditions was not influenced by blood pressure but was partly confounded by weight.. Variation in the angiotensinogen gene was modestly associated with LV mass independently of covariates in patients with hypertensive conditions. The direction of the association was opposite to that observed in patients with normotensive conditions, probably because of the influence of other risk factors or antihypertensive medication use or both.

Topics: Analysis of Variance; Angiotensinogen; Cross-Sectional Studies; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Polymorphism, Genetic; Ventricular Dysfunction, Left

To evaluate salt sensitivity in elderly subjects with different forms of hypertension and controls and to investigate any modulation by genotype. Randomized, double-blinded, placebo-controlled latin-square. Tertiary referral hospital. Community subjects (n = 46) aged > or = 60 years classified as isolated systolic hypertension [ISH; systolic blood pressure (SBP) > or = 160, diastolic blood pressure (DBP) < 90 mmHg, n = 19], diastolic +/- systolic hypertension (SDH; DBP > or = 90 mmHg, n = 10) and normotension (SBP < 160, DBP < 90 mmHg, n = 17).. Four 14 day treatments, 50, 100, 200 and 300 mmol/day of sodium chloride supplementation interspersed with 14 day washout periods on a salt-restricted diet.. The 24 h blood pressure, heart rate, weight, urinary sodium and creatinine clearance measured during baseline, treatment and washout periods and angiotensinogen (AGT) and angiotensin converting enzyme (ACE) genotypes.. For the entire cohort, the mean +/- standard error (SE) of change from baseline in SBP for 50, 100, 200 and 300 mmol/day salt was 7.7+/-2.4, 12.1+/-2.4, 16.6+/-3.0, 18.5+/-2.6 mmHg, respectively. For DBP, the respective changes were: -0.1+/-1.5, 2.4+/-1.6, 3.0+/-1.5, 5.8+/-1.7 mmHg. The increase in SBP among ISH subjects was significantly higher than among subjects in the SDH and normotensive groups (P < 0.05). AGT genotype influenced the effect of salt dose on the change in DBP (P = 0.006) but not SBP (P = 0.7).. In healthy, older subjects, a linear increase in BP occurred with increasing salt dose, it appeared most pronounced in ISH subjects and could be modulated by AGT genotype.

Topics: Aged; Angiotensinogen; Blood Pressure; Diastole; Diet, Sodium-Restricted; Double-Blind Method; Genotype; Humans; Hypertension; Middle Aged; Peptidyl-Dipeptidase A; Sodium, Dietary; Systole

To determine the relationship between angiotensinogen (ANG) genotype and blood pressure response to the dietary patterns of the Dietary Approaches to Stop Hypertension (DASH) trial. The angiotensin converting enzyme (ACE) gene was also tested.. The DASH trial was a randomized outpatient feeding study comparing the effects on blood pressure (BP) of three dietary patterns: a control diet, similar to typical American intake; a 'fruits and vegetables' diet (F/V) that is rich in fruits and vegetables but otherwise resembles the control diet; and the DASH diet that is reduced in fats and that emphasizes fruits, vegetables and low-fat dairy products. Participants' genotype was also determined.. Four clinical sites.. Adults with above-optimal BP or stage 1 hypertension.. Participants ate one of the three dietary patterns for 8 weeks. Sodium intake and weight were held constant. In 355 of 459 DASH participants, DNA was extracted from leukocytes and genotyped for the G-6A ANG polymorphism and the D/I ACE polymorphism, by the polymerase chain reaction.. Genotype at ANG and ACE loci; BP after 8 weeks of intervention diet.. There was no association between ACE genotype and BP response. Associations with ANG polymorphism were significant: net systolic and diastolic BP response to the DASH diet was greatest in individuals with the AA genotype (-6.93/-3.68 mmHg) and least in those with the GG genotype (-2.80/0.20 mmHg). A similar relationship existed for the F/V diet.. ANG genotype is associated with BP response to the DASH diet. The AA genotype confers excess risk of hypertension and is associated with increased responsiveness to diet.

Topics: Adult; Angiotensinogen; Blood Pressure; Diastole; Diet, Fat-Restricted; Female; Fruit; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Systole; Vegetables

Non-modulation has been suggested as a possible intermediate phenotype defining a subgroup of genetic hypertension. The trait is characterized by an attenuated response of renal blood flow and/or aldosterone to angiotensin (Ang) II. We tested the hypothesis that functional polymorphisms of the core promoter of the angiotensinogen gene are associated with non-modulation. Fifty-six young, white, male, untreated hypertensive patients and 65 age-matched normotensive volunteers were genotyped for 3 known functional variants of the angiotensinogen core promoter. All subjects were infused with 2 doses (0.5 and 3 ng/kg per minute) of Ang II while they were on a high sodium diet (250 mmol/d). The blood pressure, renal plasma flow, and aldosterone responses to Ang II were not affected by the -6 G/A polymorphism. The -20 A/C variant had no significant effects on the blood pressure or renal hemodynamic response to Ang II. However, the aldosterone response to both doses of Ang II was significantly decreased in -20 C allele carriers compared with -20 AA homozygotes in a multivariate analysis. The -18 T allele was not detected in our population, and there was a linkage dysequilibrium between -20 C and -6 A: -20 C almost exclusively occurred on the -6 A allele. Haplotype analysis indicated that the -20 C/-6 A haplotype but not the -20 A/-6 A haplotype was associated with a decreased aldosterone response to Ang II. We conclude that the -20 C variant or the -20 C/-6 A haplotype of the angiotensinogen core promoter is associated with a blunted aldosterone response to Ang II and may thus contribute to the non-modulating phenotype.

Topics: Adult; Aldosterone; Angiotensinogen; Angiotensins; Genetic Linkage; Genotype; Humans; Hypertension; Male; Promoter Regions, Genetic; Sodium, Dietary; Transcription, Genetic

We sought to determine whether reductions in blood pressure in hypertensives after acute exercise persist for more than the 2 to 3 h found in controlled laboratory settings. Subjects (n = 11) were obese (32 +/- 4% body fat), sedentary (VO2max 27 +/- 4 mL/kg/min) 60 +/- 6-year-old men with stage 1 or 2 essential hypertension. Ambulatory blood pressure was recorded on 1 day preceded by 45 min of 70% VO2max treadmill exercise and on another day not preceded by exercise. Systolic blood pressure was lower by 6 to 13 mm Hg for the first 16 h after exercise (P < .05) compared to the day without prior exercise. Twenty-four-hour, day, and night average systolic blood pressures were significantly lower on the day after exercise. There was a trend for peak systolic blood pressure to be lower during the entire 24 h and the day portion of the recording; peak systolic blood pressure was significantly lower during the night portion of the recording after exercise. Systolic blood pressure load (percent of systolic blood pressure readings >140 mm Hg) was reduced during the entire 24 h and the day portion of the recording after exercise. Diastolic blood pressure was lower for 12 of the first 16 h after acute exercise (hours 0 to 4, 5 to 8, 13 to 16) (P < .05) compared to the day without prior exercise. Twenty-four-hour, day, and night average diastolic blood pressure was also significantly lower on the recording after exercise. Peak diastolic blood pressure was lower over the entire 24-h period. Diastolic blood pressure load (percent of diastolic blood pressure readings >90 mm Hg) was lower during the entire 24 h and the day portion of the day after exercise. Preliminary data also suggest that common genetic polymorphisms at the angiotensinogen, lipoprotein lipase, and angiotensin converting enzyme loci may affect the blood pressure-lowering response after acute exercise. Thus, in sedentary, obese hypertensive men a single aerobic exercise session reduced blood pressure enough to result in significantly lower 24-h average systolic, diastolic, and mean arterial blood pressure. This could result in a reduced cardiovascular load during the 24 h after acute exercise in older hypertensive men.

Topics: Aged; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Exercise; Exercise Test; Heart Rate; Humans; Hypertension; Lipoprotein Lipase; Male; Middle Aged; Oxygen Consumption; Physical Endurance

The relationship of high salt intake to elevated blood pressure levels has been demonstrated in most populations by cross-sectional, longitudinal, physiological, and clinical intervention studies. Variation within the angiotensinogen gene has been implicated in the genetic control of blood pressure levels and has been suggested to contribute to increased salt sensitivity. A total of 86 hypertensive men and women who had never been treated and who had participated in a 6-month randomized, placebo-controlled, clinical trial of low-sodium mineral salt (19% reduction in urinary sodium versus 12% increase in placebo group) were genotyped at the angiotensinogen M235T locus to test the hypothesis that the 235T allele is associated with a significant blood pressure response to a sodium reduction intervention whereas the 235M allele is not. After adjustment for gender and baseline blood pressure, persons with the TT and MT genotypes showed significant systolic blood pressure reductions on mineral salt compared with control subjects (P = .02 and P = .001, respectively) but not persons with the MM genotype (P = .10). Net adjusted diastolic blood pressure reductions also showed greater significance for persons with the TT and MT genotypes than for persons with the MM genotype (P = .08, P = .01, and P = .83, respectively). The net adjusted systolic and diastolic blood pressure reduction was -8.6/-3.9 mm Hg for persons with the TT genotype, -9.0/-5.2 mm Hg for the MT genotype, and -5.3/-1.0 mm Hg for the MM genotype. We conclude that the 235T allele of the angiotensinogen gene is associated with greater blood pressure decreases than the 235M allele after a sodium reduction intervention. The angiotensinogen gene accounts for some of the interindividual variation of the blood pressure response to sodium reduction.

Topics: Aged; Alleles; Angiotensinogen; Blood Pressure; Diet, Sodium-Restricted; DNA; Double-Blind Method; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Hypertension; Magnesium; Male; Middle Aged; Potassium, Dietary; Sodium, Dietary; Treatment Outcome

A Gly460Trp variant of the cytoskeletal protein alpha-adducin has recently been implicated in the etiology of essential hypertension (HT) in a study involving southern European whites. We attempted to replicate this finding in a well-characterized, extensively studied group of 112 white Australians with essential HT, with strong family history (two HT parents), early-onset, moderate to severe disease, and of British extraction. Controls were 196 normotensive (NT) white subjects whose parents were both NT older than age 50 years. A mismatch polymerase chain reaction method involving BanII was developed for genotyping. Frequency of the Trp460 allele was 0.23 in the HT and 0.24 in the NT groups (chi2 = 0.2, P = .7). No association was observed with blood pressure, body mass index, age, plasma renin, angiotensinogen, angiotensin converting enzyme, cholesterol, triglycerides, or HDL or LDL cholesterol. Our results therefore provide no support for a role for the alpha-adducin variant in hypertension, at least in our severely affected Anglo-white group with strong family history of HT.

Topics: Alleles; Angiotensinogen; Australia; Calmodulin-Binding Proteins; Cytoskeletal Proteins; Female; Genotype; Humans; Hypertension; Lipids; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin; White People

A single-nucleotide variant of the angiotensinogen gene (AGT 235T) has been associated with essential hypertension and increased plasma levels of angiotensinogen. This variant may also serve as a genetic marker for the increased blood pressure response to dietary salt intake, but the relationship between AGT genotype and salt sensitivity has not been studied until now. We therefore examined the relationship between the AGT 235T genotype and the blood pressure response to short-term dietary salt restriction in young normotensive men.. A total of 187 young normotensive men were characterized for family history of hypertension, salt sensitivity, plasma parameters of the renin-angiotensin system under high- and low-salt diets, and the AGT 235T genotype.. While the T allele was significantly associated with a positive family history of hypertension (chi2 = 7.0; P< 0.03) and higher plasma angiotensinogen levels (P< 0.015) and renin activity (P < 0.037), blood pressure under both diets was not significantly affected by the AGT genotype. When the subjects were classified into salt-resistant and salt-sensitive groups, genotypic distribution was nearly identical between both groups (frequency of T allele: 0.45 versus 0.46).. Our findings demonstrate that the AGT 235T allele is significantly associated with a positive family history of hypertension, but is not an important determinant of the blood pressure response to dietary salt intake in young normotensive subjects. It is therefore unlikely that the AGT 235T genotype can serve as an early genetic marker of salt sensitivity.

Topics: Adult; Angiotensinogen; Blood Pressure; Cross-Over Studies; Genotype; Humans; Hypertension; Male; Point Mutation; Renin-Angiotensin System; Single-Blind Method; Sodium Chloride, Dietary; White People

There are inconsistent reports that the angiotensinogen (ATG) variant Met235-->Thr (T235) allele and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) variants are associated with hypertension and related target organ damage. Both high blood pressure (BP) and abnormal diurnal BP variation patterns are related to target organ damage, but it is not known whether the above genetic variants of the renin-angiotensin system are related to 24 h BP and the diurnal BP pattern in Japanese. We studied the association of the ATG T235 allele and ACE D allele with 24 h BP and diurnal BP variation in 235 of 262 consecutive untreated (or off medication) elderly Japanese hypertensives who underwent 24 h ambulatory BP monitoring. There was no significant association between the T235 or ACE D allele with office BP, but the T235 allele was significantly associated with 24 h BP and day BP, and the D allele was significantly associated with increased 24 h BP, day BP, and night BP. There were no effects of the T235 or D alleles on any BP parameters. Those with white-coat hypertension had a significantly lower T235 allele frequency (0.68) than those with sustained hypertension (0.79, p=0.010), but the difference in D allele frequency was marginal (0.30 vs. 0.38, p=0.057). In conclusion, in elderly Japanese hypertensive individuals, both the ATG T 235 and ACE D alleles are associated with increased 24 h BP and day BP, while only the ACE D allele is associated with increased night BP.

Topics: Aged; Alleles; Angiotensinogen; Blood Pressure; Circadian Rhythm; Female; Genotype; Humans; Hypertension; Japan; Male; Peptidyl-Dipeptidase A

Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, the T allele of a polymorphism in the 5'-flanking region of the CYP11B2 gene (C-344T) has been reported to be more frequent in hypertensives than in normotensives, and has also been associated with increased plasma aldosterone levels. We therefore hypothesized that this variant may be related to increased blood-pressure response to dietary salt intake.. We genotyped 1 63 young normotensive men recruited within the framework of the Berlin Salt-Sensitivity Trial (BeSST) for the CYP11B2 C-344T polymorphism. Subjects were characterized for family history of hypertension, plasma parameters of the renin-angiotensin-aldosterone system and blood-pressure response to a high (220 mmol/day) and low (20 mmol/day) salt diet. The frequency of the -344T allele (0.45) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (CC, n = 55; CT, n = 71; TT, n = 37). There was a trend towards a higher frequency of the T allele in subjects with a positive family history of hypertension (0.48 versus 0.42), but the C-344T genotype was not related to blood pressure under either diet Furthermore, when subjects were classified into salt-sensitive and salt-resistant groups, allelic distribution did not differ between the two groups (qT = 0.43 versus qT = 0.45). While renin activity and plasma aldosterone levels were not related to genotype, plasma angiotensinogen was significantly higher in T-allele carriers under both the high (P = 0.02) and low (P = 0.008) salt diet.. Our findings do not support the hypothesis that the C-344T polymorphism of the CYP11B2 gene is associated with salt sensitivity or increased activity of the renin-angiotensin system in young normotensive subjects. It is, therefore, unlikely that the C-344T polymorphism is a genetic marker for salt sensitivity in young normotensive Caucasian men.

Topics: Adult; Aldosterone; Alleles; Angiotensinogen; Anthropometry; Blood Pressure; Cross-Over Studies; Cytochrome P-450 CYP11B2; Diet, Sodium-Restricted; Drug Resistance; Gene Frequency; Genotype; Humans; Hypertension; Male; Polymorphism, Genetic; Renin; Single-Blind Method; Sodium Chloride; White People

Previous studies have reported tight linkage disequilibrium between the T235 and the A(-6) molecular variants of the angiotensinogen gene. This study was designed primarily to ascertain whether a similar relationship exists between the M235 and the G(-6) variants of the gene. We have investigated the degree of agreement between the genotypes of the M235T and the G(-6)A polymorphisms in two ethnic groups.. Subjects were an heterogeneous group of normotensive and hypertensive subjects of Caucasian (n = 77) and Afro-Caribbean (n = 51) origin. DNA was extracted from whole blood and was genotyped for both the M235T and G(-6)A polymorphisms using PCR-based methods.. The distribution frequencies of the MM, MT, and TT genotypes were 0.39, 0.42, and 0.20 in white subjects, and 0.09, 0.17, and 0.74 in black subjects, respectively (chi-square, P < 0.0001). The distribution of AA, GA, and GG genotypes also differed between the two groups as follows: 0.22, 0.48, and 0.30 in white subjects, and 0.82 and 0.18 and 0 in black subjects respectively (chi-square, P < 0.0001). The agreement for TT-AA, MT-GA, and MM-GG was 93%, 91%, and 76% respectively in white and 100%, 67% and 0% respectively in black subjects.. The results indicate ethnic differences in the distribution of both M235T and G(-6)A genotypes. The trend towards a decrease in the degree of agreement in the order of TT-AA > MT-GA > MM-GG suggests that linkage disequilibrium between the M235 and G-6 variant does not mirror that observed with the T235 and A-6 variants. These observations may have significant implications regarding the associations between the G(-6)A polymorphism and hypertension. However, this needs to be further investigated.

Topics: Angiotensinogen; Black People; Caribbean Region; Chi-Square Distribution; Female; Gene Expression; Genotype; Humans; Hypertension; Male; Polymorphism, Genetic; Sensitivity and Specificity; United Kingdom; White People

Although the relationship between an increase in adipose tissue and a rise in blood pressure has long been recognized, the mechanism linking these two phenomena has yet to be fully understood. Recently, it has become evident that adipose tissue is a rich source of metabolically active molecules, including free fatty acids, leptin and angiotensinogen, the precursor of angiotensin II. The latter finding has prompted speculation on the possible role of adipocyte-derived angiotensinogen in the relationship between body weight and blood pressure. Therefore we examined the relationship between blood pressure, angiotensinogen, body mass index (BMI) and leptin levels in healthy normotensive subjects who are genetically predisposed to the development of hypertension.. We studied 40 subjects with a positive family history of hypertension and 51 subjects with a negative family history. After the blood pressure measurements, blood samples were collected for the assessment of angiotensinogen, leptin, glucose, insulin, renin activity and electrolytes. Oral glucose tolerance was studied by an oral glucose tolerance test (75 g glucose).. Plasma angiotensinogen was significantly correlated with both BMI (r=0.29, P < 0.01) and plasma leptin (r=0.40, P < 0.001). While plasma angiotensinogen and blood pressure were positively correlated only in subjects with a positive family history of hypertension (r=0.33, P< 0.05), plasma leptin was related to blood pressure in both groups (r=0.26, P=0.01). Furthermore, the insulin response to an oral glucose load was significantly related to both plasma angiotensinogen (r=0.22, P< 0.05) and plasma leptin (r=0.47, P< 0.001).. These findings support the hypothesis that circulating angiotensinogen levels are related to adipose mass in young, normotensive, nonobese men. Further studies on the relationship between adipose tissue and systemic or local renin-angiotensin systems appear warranted.

Topics: Adipose Tissue; Adult; Angiotensinogen; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Electrolytes; Genetic Predisposition to Disease; Humans; Hypertension; Insulin; Leptin; Male; Proteins; Reference Values; Renin

A close relationship between obesity and hypertension has been recognized, and plasma angiotensinogen concentrations (p-AGT) have been reported to correlate with blood pressure (BP). However, little is known about AGT in obese patients with hypertension. To define the role of AGT in obese hypertension, we measured p-AGT in obese patients. The subjects were 42 obese patients diagnosed on the basis of a body mass index (BMI) of more than 25 kg/m2, and 21 sex- and age-matched nonobese patients, whose BMI was less than 25 kg/m2. The hypertensive patients had not previously received antihypertensive drugs. P-AGT (P < .05) and mean BP (P < .0001) was increased in the obese patients as compared with the nonobese patients. Positive correlations were observed between BMI and p-AGT, mean BP and p-AGT, and BMI and mean BP (all P < .05). However, after adjustment for blood pressure, p-AGT was not different between groups, and after adjustment a positive correlation remained only between BMI and mean BP. These results suggested the possible involvement of increased p-AGT in hypertension in obese patients, although this may be a secondary change to hypertension or obesity.

Topics: Adult; Angiotensinogen; Blood Pressure; Body Mass Index; Female; Humans; Hypertension; Male; Middle Aged; Obesity

Our paper is discussing the presence and intensity of metabolic, humoral and haemodynamic abnormalities in mild middle-aged essential hypertensives (EH) and in hereditary predisposed still normotensive offspring from hypertensive families and their possible association with candidate genes changes. Four groups of subjects were compared (middle-aged normotensive controls (n = 21), corresponding patients with EH (n = 21), normotensive offspring from hypertensive (SH) (n = 56) and normotensive families (SN) (n = 56). Our results demonstrate that middle-aged patients with EH in our country have the same indices of hyperinsulinemia, impared glucose tolerance and insulin-sensitivity as previously described for other populations. They are accompanied by higher plasma concentrations of vasopressor substance like catecholamines, endothelin and lower levels of vasodepressor substances as ANP and kallikrein. The finding of similar, but quantitatively less expressed metabolic and humoral changes in SH but not in SN support the evidence for hereditary background of these abnormalities. The humoral and metabolic abnormalities may participate in BP elevation and in morphological and functional changes of left ventricle seen in SH (higher LV mass index, impaired diastolic filling). We did not prove an association between BP and polymorphism of ACE and angiotensinogen genes, however, our findings of association of DD genotype for ACE and M235 for angiotensinogen with higher insulinemia, plasma catecholamines and plasma renin activity evoke the hypothesis, whether the bearers of these genotypes, exposed for long-time to the higher concentrations of vascoactive substances, are not the subset of hereditary threatened subjects in whom clinically evident EH will manifest during their life.

Topics: Adult; Angiotensinogen; C-Peptide; Disease Susceptibility; Echocardiography; Epinephrine; Genotype; Humans; Hyperinsulinism; Hypertension; Kallikreins; Male; Norepinephrine; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To investigate whether the M235T polymorphism of the angiotensinogen (AGT) gene and the insertion/deletion (I/D) polymorphism of the angiotensin-1 converting enzyme (ACE) gene predict blood pressure response to different antihypertensive agents.. Sixty-three patients with untreated essential hypertension were randomly assigned in a placebo-controlled crossover comparison to atenolol 50 mg once daily, lisinopril 10 mg once daily and nifedipine SR 20 mg twice daily, and the effect on blood pressure was assessed by ambulatory blood pressure monitoring (ABPM). In a further 44 patients, placebo-controlled ABPM data were available after treatment with a single agent (atenolol 50 mg once daily in 16 cases and lisinopril 10mg once daily in 28 cases). The change in systolic and diastolic blood pressure achieved by each agent was analysed for association with genotypes at the AGT and ACE gene loci.. Polymerase chain reaction (PCR) amplification of genomic DNA from each individual was used to identify the I/D polymorphism of the ACE gene. The M235T polymorphism of the AGT gene was detected by Tth111I digestion of PCR product.. There was no significant association between response to any drug and either the AGT M235T or ACE I/D polymorphisms.. The large variability between individuals in the observed blood pressure response to these agents cannot be attributed to the polymorphisms analysed at the ACE and AGT loci.

Topics: Alleles; Analysis of Variance; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; DNA; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Renin-Angiotensin System

The angiotensinogen gene locus (1q42-43) has been linked to hypertension in affected relative-pair studies (including a previous UK study), but the role of the Met-->Thr polymorphism at position 235 remains controversial. Using this marker, we investigated the relationship between angiotensinogen genotype and blood pressure in two data sets from the East Anglia region of the United Kingdom. Two hundred twenty-three untreated hypertensive and 187 normotensive control subjects were recruited through local general practices. Blood pressure (including pretreatment measurements in the hypertensive group), age, sex, body mass index, alcohol consumption, cholesterol level, and angiotensinogen genotype were recorded for all subjects. The influence of angiotensinogen genotype on blood pressure was assessed with a general linear model ANOVA with adjustment for age, sex, body mass index, and alcohol consumption. There was no evidence for an association between angiotensinogen genotype and blood pressure level in either the hypertensive or normotensive data set. Angiotensinogen genotype did not influence blood pressure in subjects aged < 50 years, women, or those with a body mass index < 26 kg/m2. We conclude that the angiotensinogen Met-->Thr polymorphism is not a marker for blood pressure level in these East Anglian subjects. Further studies are required to confirm the involvement of the 1q locus in the development of hypertension in UK subjects and to delineate the functional variant(s) in this chromosomal region that influences blood pressure.

Topics: Angiotensinogen; Blood Pressure; Female; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

The frequency of the 235T and 174M alleles of the angiotensinogen gene, previously reported to be associated with hypertension in Caucasians and Japanese, was compared between 57 hypertensive African Americans and 130 normotensive African Americans sampled as part of a community survey of hypertension in the Chicago area. The frequency of the 235T allele was unrelated to hypertension status (cases, 83%, control subjects, 82%), as was true for the 174M allele. Compared with Caucasians, the frequency of the 235T allele was twice as high in this African American population, while the frequency of the 174M allele was similar. Even higher frequencies of the 235T allele (93%) were noted in a sample of 122 Nigerians. It appears that the 235T allele is very common in populations of West African origin, although we found no evidence that it confers risk of hypertension.

Topics: Adult; Aged; Alleles; Angiotensinogen; Base Sequence; Black People; Chicago; DNA; Female; Genetic Variation; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Nigeria; Oligonucleotide Probes; Polymorphism, Genetic; Reference Values

Topics: Adult; Alleles; Angiotensinogen; Double-Blind Method; Enalapril; Female; Gene Frequency; Genetic Variation; Humans; Hypertension; Male; Middle Aged; Point Mutation

Forty-six patients were randomly allocated to two different groups of treatment if their diastolic blood pressure remained above 90 mm Hg after one month of treatment with 20 mg enalapril mg once daily. In the first group (ENA), 23 patients were given higher daily dosages of enalapril (40 mg and, when necessary, 60 mg). The second group of 23 patients (HCTZ) was given 20 mg/day enalapril and hydrochlorothiazide (25 mg/day and, when necessary, 50 mg). Blood pressure was measured by an automatic device and by the physician with a standard sphygmomanometer. Blood pressure was significantly lower in the HCTZ group, according to both the automatic device (130 +/- 9/80 +/- 8 vs. 141 +/- 5/86 +/- 8 mm Hg, p less than 0.01/p less than 0.05) and the sphygmomanometer (134 +/- 10/89 +/- 6 vs. 149 +/- 16/94 +/- 5 mm Hg, p less than 0.001/p less than 0.01). Plasma renin activity, increased by enalapril at the 20 mg dosage, rose in the HCTZ group but not in the ENA group (22.4 +/- 22 vs. 10.2 +/- 11 pmol/ml/h, p less than 0.05). Plasma aldosterone increased significantly in the HCTZ group (0.44 +/- 0.22 vs. 0.30 +/- 0.17 pmol/ml, p less than 0.05) but did not change in the ENA group (0.31 +/- 0.11 vs. 0.30 +/- 0.17 pmol/ml, NS). In the ENA group, converting enzyme activity was not reinforced (5.7 +/- 8 vs. 6.6 +/- 6 mU/ml, NS) despite an increase in plasma enalaprilat levels (172.4 +/- 108 vs. 72.1 +/- 42 ng/ml, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensinogen; Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Random Allocation; Renin; Renin-Angiotensin System

The effect of captopril on blood pressure (BP) and various components of the renin-angiotensin system was assessed in ten severely hypertensive patients. Captopril acutely reduced the BP with a maximum decrease of 23% at 90-120 min. Maintenance treatment with captopril alone could not control the BP in any of the patients. Addition of hydrochlorothiazide markedly reduced the BP, while supplementation with propranolol caused no consistent changes. Three patients attained a supine diastolic blood pressure (SDBP) less than or equal to 90 mmHg. Only two patients had a fall in SDBP less than 10 mmHg. One patient stopped because of taste disturbances. Monitoring the renin-angiotensin system showed suppressed plasma concentrations of angiotensin II and increased levels of angiotensin I and renin, indicating the inhibition of converting enzyme activity. Plasma concentration of renin substrate decreased significantly. This observation has important implications for the methodology of renin assays. Captopril is an effective alternative in the treatment of hypertensive patients not readily controlled with conventional therapy.

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Captopril; Drug Resistance; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Proline; Propranolol; Renin; Renin-Angiotensin System

Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension.. The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort.. Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively.. Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65).. Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes.

Topics: Adult; Aldosterone; Angiotensinogen; Atherosclerosis; Blood Pressure; Female; Humans; Hypertension; Male; Renin-Angiotensin System

Topics: Angiotensinogen; Atherosclerosis; Humans; Hypertension

High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD. FK228 also blocked upregulation of renal Agt mRNA, protein, angiotensin II (Ang II) or serum Ang II. Activation and nuclear accumulation of both HDAC1 and HDAC2 occurred in the HFD group. The HFD-induced HDAC activation was associated with an increase in deacetylated c-Myc transcription factor. Silencing of HDAC1, HDAC2 or c-Myc in HRPTEpi cells decreased Agt expression. However, only HDAC1 knockdown, but not HDAC2, increased c-Myc acetylation, suggesting selective roles in two enzymes. Chromatin immunoprecipitation assay revealed that HFD induced the binding of HDAC1 and deacetylated c-Myc at the Agt gene promoter. A putative c-Myc binding sequence in the promotor region was necessary for Agt transcription. Inhibition of c-Myc downregulated Agt and Ang II levels in kidney and serum, ameliorating HFD-induced hypertension. Thus, the abnormal HDAC1/2 in the kidney may be responsible for the upregulation of the Agt gene expression and hypertension. The results expose the pathologic HDAC1/c-myc signaling axis in kidney as a promising therapeutic target for obesity-associated resistant hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Diet, High-Fat; Hypertension; Male; Mice; Mice, Inbred C57BL; Obesity; Proto-Oncogene Proteins c-myc; Signal Transduction

Topics: Angiotensinogen; Blood Pressure; Humans; Hypertension

Obesity is associated with hypertension. However, the mechanisms involved are not fully understood. Therefore, we investigated the relationship between obesity and vasoactive mediators. In this cross-sectional study, blood pressure (BP) and vasoactive mediators of hypertension are compared among 135 adults in the nonobese, obese, and morbidly obese body mass index (BMI) ranges (BMI ≤27, 30-40, and >40 kg/m

Topics: Adult; Aldosterone; Angiotensin II; Angiotensinogen; Blood Pressure; Cross-Sectional Studies; Humans; Hypertension; Male; Neprilysin; Obesity, Morbid; Renin; Renin-Angiotensin System; Vasoconstrictor Agents; Vasodilator Agents

Hypertension (HTN) is a multifactorial chronic disease that poses a significant global health burden and is associated with increased mortality rates. It often coexists with other conditions, such as cardiovascular, liver, and renal diseases, and has a strong association with diabetes mellitus. Insulin resistance and endothelial dysfunction commonly occur in individuals with both HTN and type 2 diabetes mellitus (T2DM). Genetic factors, along with environmental and pathological factors, play a role in the development of HTN. Recent studies have revealed the influence of single nucleotide polymorphisms (SNPs) in various genes on HTN. In this study, we aimed to investigate the genetic polymorphism of angiotensinogen (AGT) T174M (rs4762) and its association with HTN in diabetic patients.. A total of 300 participants were enrolled in this study and divided into three groups: control, hypertensive, and hypertensive diabetic. Blood samples were collected, and predetermined biochemical parameters were assessed. Genotyping of the AGT T174M (rs4762) gene was conducted using Tetra ARMS PCR with specific primers.. The study findings revealed a significant association between AGT T174M (rs4762) genotype and HTN in diabetic patients within the Pakistani population. The C/T genotype of AGT T174M (rs4762) was found to be significant in both the hypertensive and hypertensive diabetic participants compared to the control group. This genotype was identified as a risk factor for developing HTN in both the hypertensive and hypertensive diabetic participants.. This study demonstrates a significant association between AGT T174M (rs4762) genetic polymorphism and HTN in diabetic patients. The C/T genotype of AGT T174M (rs4762) may serve as a potential marker for identifying individuals at risk of developing HTN, specifically in the hypertensive and hypertensive diabetic populations. Further research is warranted to elucidate the underlying mechanisms and validate these findings in larger cohorts.

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Humans; Hypertension; Insulin Resistance; Polymorphism, Single Nucleotide

We engineered a monoclonal antibody (mAb) against the human C-terminus of angiotensin-(1-12) [h-Ang-(1-12)] and performed a biochemical characterization in concert with direct in vivo and ex vivo (carotid artery strips) assessments of h-Ang-(1-12) vasoconstrictor activity in 78 (36 females) transgenic rats expressing the human angiotensinogen gene [TGR(hAGT)L1623] and 26 (10 female) Sprague Dawley (SD) controls. The mAb shows high specificity in neutralizing angiotensin II formation from h-Ang-(1-12) and did not cross-react with human and rat angiotensins. Changes in arterial pressure and heart rate in Inactin® hydrate anesthetized rats were measured before and after h-Ang-(1-12) injections [dose range: 75-300 pmol/kg i.v.] prior to and 30-60 minutes after administration of the h-Ang-(1-12) mAb. Neutralization of circulating Ang-(1-12) inhibited the pressor action of h-Ang-(1-12), prevented Ang-(1-12) constrictor responses in carotid artery rings in both SD and TGR(hAGT)L1623 rats, and caused a fall in the arterial pressure of male and female transgenic rats. The Ang-(1-12) mAb did not affect the response of comparable dose-related pressor responses to Ang II, pre-immune IgG, or the rat sequence of Ang-(1-12). This h-Ang-(1-12) mAb can effectively suppress the pressor actions of the substrate in the circulation of hypertensive rats or in carotid artery strips from both SD and transgenic rats. The demonstration that this Ang-(1-12) mAb by itself, induced a fall in arterial pressure in transgenic hypertensive rats supports further exploring the potential abilities of Ang-(1-12) mAb in the treatment of hypertension.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Antibodies, Monoclonal; Blood Pressure; Female; Humans; Hypertension; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley

Exercise training (Ex) has antihypertensive and renal protective effects; however, the precise mechanisms remain unclear. The renal renin-angiotensin system (RAS) plays a vital role in renal function and pathology. Therefore, we investigated the effects of Ex on the renal RAS components in Dahl salt-sensitive (Dahl-S) rats.. Male Dahl-S rats were divided into four groups: normal salt diet + sedentary, normal salt diet + Ex, high-salt diet (HS, 8% NaCl) + sedentary, and HS + Ex. Treadmill running was performed for 8 wk in the Ex groups.. Ex attenuated the HS-induced renal dysfunction and glomerular injury without causing blood pressure alterations. HS increased urinary excretion of both total and intact angiotensinogen. Ex decreased the HS-induced increased urinary excretion of total angiotensinogen. However, it did not change the HS-induced urinary excretion of intact angiotensinogen, indicating reduced intact angiotensinogen cleaving. Ex restored the HS-induced increased angiotensinogen and angiotensin II type 1 receptor expressions in the outer medulla and the HS-induced increased angiotensin-converting enzyme expression in the cortex. Ex restored the HS-induced decreased renin expression in the cortex and outer medulla, and the HS-induced decreased angiotensin-converting enzyme 2, angiotensin II type 2 receptor, and Mas receptor expressions in the outer medulla.. Ex attenuates HS-induced renal dysfunction, glomerular injury, and renal RAS dysregulation in Dahl-S rats.

Topics: Angiotensinogen; Animals; Blood Pressure; Hypertension; Kidney; Male; Physical Conditioning, Animal; Rats; Rats, Inbred Dahl; Renin-Angiotensin System

An association between genetic variants in the genes HFE, HJV, BMP4 and arterial hypertension has been shown earlier. Proteins encoded by these genes participate in the signalling routes leading eventually to the production of the peptide hormone hepcidin. Mutations in these genes have been associated with the abnormal production of hepcidin in the body. This finding led to studies exploring the possible role of hepcidin in regulating the activity of blood pressure related renin-angiotensin system enzymes. We used molecular modelling to find out if it is possible for hepcidin to bind to the active site of the renin-angiotensin system enzymes, especially renin. Fluorometric assays were used to evaluate the inhibitory effect of hepcidin on renin as well as angiotensin converting enzymes 1 and 2. Finally, bio-layer interferometry technique was used to study hepcidin binding to renin. The molecular modelling showed that hepcidin seems to have similar binding properties to the renin active site as angiotensinogen does. Based on fluorometric enzyme activity assay, hepcidin has an inhibitory effect on renin in vitro, too. However, angiotensin converting enzymes 1 and 2 were not inhibited remarkably by hepcidin-25. In bio-layer interferometry analysis hepcidin-renin binding was concentration dependent. Our results suggest that hepcidin could act as an inhibitor to the renin. Nowadays, there is no known biological inhibitor for renin in vivo and our finding may thus have important clinical implications.

Topics: Angiotensinogen; Blood Pressure; Hepcidins; Humans; Hypertension; Renin; Renin-Angiotensin System

High blood pressure is widely regarded as the most important risk factor for cardiovascular diseases. Epistasis analysis may provide additional insight into the genetic basis of hypertension.. A nested case-control design was used on 4214 unrelated Tehran Cardiometabolic Genetic Study (TCGS) adults to evaluate 65 SNPs of previously associated genes, including ZBED9, AGT, and TNXB. The integrated effect of each gene was determined using the Sequence-based Kernel Association Test (SKAT). We used model-based multifactor dimension reduction (Mb-MDR) and entropy-based gene-gene interaction (IGENT) methods to determine interaction and epistasis patterns.. The integrated effect of each gene has a statistically significant association with blood pressure traits (P-value < 0.05). The single-locus analysis identified two missense variants in ZBED9 (rs450630) and AGT (rs4762) associated with hypertension. In the ZBED9 gene, significant local interactions were discovered. The G allele in rs450630 showed an antagonistic effect on hypertension, but interestingly, IGENT analysis revealed significant epistasis effects for different combinations of ZBED9, AGT, and TNXB loci.. We discovered a novel interaction effect between a significant variant in an essential gene for hypertension (AGT) and a missense variant in ZBED9, which has shifted our focus to ZBED9's role in blood pressure regulation.

Topics: Adult; Angiotensinogen; Blood Pressure; Epistasis, Genetic; Genetic Predisposition to Disease; Humans; Hypertension; Iran

Hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. Angiotensinogen and renin are key components of the renin-angiotensin-aldosterone system, which plays an indispensable role in hypertension. The aim of this study was to find out the non-synonymous mutations and structure-based mutation-function correlation in the renin-AGT complex and reveal the most deleterious mutations to accelerated hypertension. In the current study, we employed computational modeling and molecular simulation approaches to demonstrate the impact of specific mutations in the REN-AGT interface in hypertension. Computational algorithms, that is, PhD-SNP, PolyPhen-1, MAPP, Sorting Intolerant from Tolerant, Screening of non-acceptable polymorphism, PredictSNP, PolyPhen-2, and Protein Analysis Through Evolutionary Relationships predicted 20 mutations as deleterious in AGT while only five mutations were confirmed as deleterious in the renin protein. Investigation of the bonding analysis revealed that two mutations S107L and V193F in renin altered the hydrogen-bonding paradigm at the interface site. Furthermore, exploration of structural-dynamic behaviors demonstrated by that these mutations also increases the structural stability to regulate the expression of disease pathway. The flexibility index of each residues and structural compactness analysis further validated the findings by portraying the difference in the dynamic behavior in contrast to the wild type. Binding energy calculations based on molecular mechanics/generalized Born surface area methods were used which further established the binding differences between the wild type, S107L, and V193F mutant variants. The total binding energy for wild type, S107L, and V193F was reported to be -27.79, -47.72, and -38.25, respectively. In conclusion, these two mutations increase the binding free energy alongside the docking score to enhance the binding between renin and AGT to overexpress this pathway in a hypertension disease condition. Patients with these mutations may be screened for potential therapeutic intervention.

Topics: Angiotensinogen; Humans; Hydrogen; Hypertension; Renin; Renin-Angiotensin System

Hypertension occurred in 50% obstructive sleep apnea-hypopnea syndrome (OSAHS) patients meanwhile OSAHS occurred in 30% hypertension patients. The present study aimed to explore the molecular mechanism of GATA2-EDN1-AGT induced hypertension in the development of obstructive sleep apnea-hypopnea syndrome. OSAHS patients (56 cases: 36 cases of male, 20 cases of female, 42~60 years old) were divided into two groups (case group: patients with hypertension monitored by 24 h ambulatory blood pressure and polysomnography; control group: patients without hypertension). Wistar rats were used to establish the OSAHS model (narrow pharyngeal cavity). PaO2 and PaCO2 of patients and rats were measured by an automatic blood gas analyzer. The profile of total protein in the OSAHS group and normal group was evaluated. Protein-protein-interaction (PPI) was carried out to show all matter proteins related. The levels of EDN-1, AGTII and atrial natriuretic peptide (ANP) in blood samples of patients and rats were analyzed by enzyme-linked immunosorbent assay (ELISA). The expression of GATA2, EDN1, endothelin-converting enzyme 1 (ECE-1) and AGTⅡ was measured. The results showed that SaO2 and AHI were positively associated with systolic pressure (P<0.05) in OSAHS patients. There was no correlation among other indexes (P>0.05). It was also observed that GATA2 had a strong relationship with AGTⅡ and EDN1. The results of ELISA presented that the levels of EDN1, AGTⅡ and ANP in the OSAHS group of human and animal models were significantly increased (P<0.05). The results of immunochemistry showed that the expression of GATA2 and AGTⅡ in the vascular of OSAHS group was upregulated manifestly (P<0.05). It was concluded that OSAHS can induce AHI, which increases hypertension via the GATA2-EDN1-AGT Ⅱ axis.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Endothelin-1; Female; GATA2 Transcription Factor; Hypertension; Male; Rats; Rats, Wistar; Sleep Apnea, Obstructive; Syndrome

Background A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogen and lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensin rise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressors can raise arterial pressure after angiotensinogen depletion. Methods and Results Spontaneously hypertensive rats on a low-salt diet were treated with siRNA (10 mg/kg fortnightly) for 4 weeks, supplemented during the final 2 weeks with fludrocortisone (6 mg/kg per day), the α-adrenergic agonist midodrine (4 mg/kg per day), or a high-salt diet (all groups n=6-7). Pressor responsiveness to angiotensin II and norepinephrine was assessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogen by siRNA lowered plasma angiotensinogen concentrations by 99.2±0.1% and mean arterial pressure by 19 mm Hg. siRNA-mediated blood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversed by fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasma angiotensinogen concentrations in siRNA-treated rats, and nearly abolished plasma renin concentrations. To investigate whether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepatic angiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen in the siRNA-treated rats must have depended on the liver, most likely reflecting diminished cleavage by renin. Conclusions Intact pressor responsiveness to conventional vasopressors provides pharmacological means to regulate the blood pressure-lowering effect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Fludrocortisone; Hypertension; Mice; Midodrine; Norepinephrine; Rats; Renin; Renin-Angiotensin System; RNA, Small Interfering; Vasoconstrictor Agents

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Immunosuppression Therapy; Kidney; Kidney Diseases; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger

Topics: Angiotensinogen; Animals; Blood Pressure; Humans; Hypertension; Rats; Rats, Inbred SHR; RNA, Small Interfering; Vasoconstrictor Agents

The study aim was to analyse the frequency of polymorphic variants of angiotensinogen gene polymorphism (AGT 704T>C, rs699) in essential arterial hypertension (EAH) patients.. Seventy-two individuals with EAH and hypertension‑mediated organ damage (stage 2), moderate, high or very high cardiovascular risks were involved in the case-control study. Among them, 70.84 % (51) were females and 29.16 % (21) were males; mean age was 59.87±7.98 y. The control group consisted of fifty practically healthy individuals at relevant age (49.13±6.28 y) and with relevant sex distribution (62 % were females, 38 % were males). AGT (704T>C) gene polymorphism was examined by RT-PCR.. The distribution of genotypes in the study group was as follows: TT - 14 %, TC - 60 %, CC - 26 %, which corresponded to the distribution in the control group - 16 %, 54 % and 30 %, respectively, and did not deviate from the Hardy-Weinberg equilibrium. Smoking, type 2 diabetes mellitus (DM2) and obesity increased the relative risk of EAH in the examined population 2.5 times [OR=2.81; p=0.049], 3.75 times [OR=4.68; p=0.005] and almost twofold [OR=2.90; p=0.004], respectively. The probability of EAH increases fourfold with the angiotensin II elevation in the serum. Genotypes and alleles of the AGT (704T>C) gene were not significant risk factors for EAH and DM2 in the studied population. However, the TC-genotype (lesser T-allele) increases the risk of obesity in EAH patients more than 1.5 times [OR=2.93; p=0.03]. In addition, the T-allele increases the risk for blood pressure (BP) to elevate up to grade 2-3 [OR=3.64; p < 0.001].. One-way ANOVA analysis confirmed the AGT (704T>C) gene polymorphism to be associated with systolic and diastolic BP elevation (F=7.80; p < 0.001 and F=4.90; p=0.01, respectively), especially in TT-genotype carriers (p < 0.05), and with body mass index increase, albeit only in women (F=13.94; p < 0.001) (Tab. 4, Fig. 3, Ref. 26). Text in PDF www.elis.sk Keywords: angiotensinogen gene (AGT 704T>C), diabetes mellitus type 2, arterial hypertension, obesity, risk.

Topics: Aged; Angiotensinogen; Blood Pressure; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Obesity; Polymorphism, Genetic

[Figure: see text].

Topics: Adolescent; Adult; Aged; Aldosterone; Alleles; Angiotensinogen; Blood Pressure; Estrogen Receptor beta; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Sodium Chloride, Dietary; Young Adult

Functional variants in genes of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems have already been implicated in blood pressure (BP) modulation, but few studies have focused on a nutrigenetics approach. Thus, the aim of this study is to verify the effects of the interaction between genetic polymorphisms (rs4340-ACE, rs699-AGT, and rs1799722-BDKRB2) and micronutrient consumption (sodium, potassium, calcium, and magnesium) on BP values of normotensive adult individuals. The study included 335 adults, men and women, 25.5 (6.6) years old. Biochemical, anthropometric, BP measurements, and food intake data were assessed for all participants. Gene-nutrient interaction on BP outcome was tested by multiple linear regression with manual backward stepwise modeling. Our results indicated that individuals with G allele for rs699 polymorphism, in the increase of sodium and magnesium consumption, both in the genotypic model (sodium, p = 0.035; magnesium, p = 0.016) and in the dominant model (sodium, p = 0.009; magnesium, p = 0.006) had higher systolic BP (SBP) levels compared to AA homozygotes (sodium, p = 0.001; magnesium, p < 0.001). Also, individuals with the T allele for the rs1799722 polymorphism, with higher calcium intake, had significantly higher levels of SBP and diastolic BP (DBP) when compared to CC homozygotes (p = 0.037). In conclusion, our findings pointed for significant interactions between genetic polymorphisms (rs699-AGT and rs1799722-BDKRB2) and the consumption of micronutrients (sodium, magnesium, and calcium) on the BP variation. These findings contribute to the understanding of the complex mechanisms involved in BP regulation, which probable include several gene-nutrition interactions.

Topics: Adult; Angiotensinogen; Blood Pressure; Calcium; Cross-Sectional Studies; Diet; Female; Humans; Hypertension; Magnesium; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Potassium; Receptor, Bradykinin B2; Sodium

Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 ± 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation.

Topics: Angiotensin II; Angiotensinogen; Animals; Brain; Brain Stem; Desoxycorticosterone Acetate; Hypertension; Male; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Valsartan

Circadian fluctuation disorder of the intrarenal renin-angiotensin system (RAS) causes that of blood pressure (BP) and renal damage. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen (AGT) filtered through damaged glomeruli regulates intrarenal RAS activity. Furthermore, glomerular permeability is more strongly affected by glomerular hypertension than by systemic hypertension. Thus, we aimed to clarify whether the circadian rhythm of intrarenal RAS activity is influenced by AGT filtered through damaged glomeruli due to glomerular capillary pressure. Rats with adriamycin nephropathy and an impaired glomerular filtration barrier were compared with control rats. In adriamycin nephropathy rats, olmesartan medoxomil (an angiotensin II type 1 receptor blocker) or hydralazine (a vasodilator) was administered, and the levels of intrarenal RAS components in the active and rest phases were evaluated. Moreover, the diameter ratio of afferent to efferent arterioles (A/E ratio), an indicator of glomerular capillary pressure, and the glomerular sieving coefficient (GSC) based on multiphoton microscopy in vivo imaging, which reflects glomerular permeability, were determined. Mild renal dysfunction was induced, and the systemic BP increased, resulting in increased A/E ratios in the adriamycin nephropathy rats compared with the control rats. Fluctuations in intrarenal RAS activity occurred in parallel with circadian fluctuations in glomerular capillary pressure, which disappeared with olmesartan treatment and were maintained with hydralazine treatment. Furthermore, the GSCs for AGT also showed similar changes. In conclusion, intrarenal RAS activity is influenced by the filtration of liver-derived AGT from damaged glomeruli due to circadian fluctuation disorder of the glomerular capillary pressure.

Topics: Angiotensinogen; Animals; Circadian Rhythm; Doxorubicin; Glomerular Filtration Rate; Hydralazine; Hypertension; Kidney Diseases; Liver; Rats; Renin-Angiotensin System

Type 2 diabetes mellitus (T2DM) and hypertension are common chronic diseases mainly associated with the development and progression of end-stage renal disease (ESRD) leading to morbidity and mortality. Gene polymorphisms linked to the renin-angiotensin (

Topics: Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Egypt; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Mutation, Missense; Polymorphism, Single Nucleotide

The dodecapeptide angiotensin-(1-12) [Ang-(1-12)] functions as an intracrine/paracrine substrate for local production of angiotensin II. We developed a reliable and specific radioimmunoassay (RIA) method for the measurement of Ang-(1-12) in human plasma and urine using an affinity purified antibody fraction directed towards the C-terminus of the human Ang-(1-12) sequence. The RIA method was applied to quantify the Ang-(1-12) in plasma and urine collected from thirty-four human subjects (29 treated with antihypertensive medicines and 5 untreated patients). Plasma Ang-(1-12) level was significantly higher (P < 0.05) in patients with systolic blood pressure ≥140 mm Hg (n = 10) compared to the group with systolic blood pressure <140 mm Hg (n = 24). No significant difference (P = 0.22) was found in spot urine between the groups. Our study also shows that the polyclonal antibody neutralizes the cleavage sites of the human Ang-(1-12) from recombinant human chymase (rhChymase) and serum angiotensin converting enzyme (ACE) mediated Ang II generating hydrolysis. Overall, this newly developed RIA method is reliable and applicable to accurately quantify the Ang-(1-12) level in clinical samples (plasma and urine). Further, our in vitro neutralization study suggests that the anti-Ang-(1-12)-antibody might be used as an in vivo therapeutic agent for preventing Ang-(1-12)/Ang II-mediated hypertension and organ damage.

Topics: Aged; Angiotensin II; Angiotensinogen; Antibodies; Antihypertensive Agents; Blood Pressure; Case-Control Studies; Chymases; Female; Gene Expression Regulation; Humans; Hypertension; Limit of Detection; Male; Middle Aged; Peptide Fragments; Radioimmunoassay; Recombinant Proteins; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance

[Figure: see text].

Topics: Angiotensinogen; Animals; Cell Line; CRISPR-Cas Systems; Gene Deletion; Hypertension; Liver; Rats; Rats, Wistar

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Chymases; Diabetic Nephropathies; Gene Expression Regulation; Humans; Hypertension; Kidney; Peptide Fragments; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance

During type 2 diabetes (T2D) and hypertension there is stimulation of renal proximal tubule angiotensinogen (AGT), but whether urinary excretion of AGT (uAGT) is an indicator of glomerular damage or intrarenal RAS activation is unclear. We tested the hypothesis that elevations in uAGT can be detected in the absence of albuminuria in a mouse model of T2D.. Male C57BL/6 mice (N = 10) were fed a high fat (HFD; 45% Kcal from fat) for 28 weeks, and the metabolic phenotype including body weight, blood pressures, glucose, insulin, ippGTT, HOMA-IR, and cholesterol was examined. In addition, kidney Ang II content and reactive oxygen species (ROS) was measured along with urinary albumin, creatinine, Ang II, and AGT.. All parameters consistent with T2D were present in mice after 12-14 weeks on the HFD. Systolic BP increased after 18 weeks in HFD but not NFD mice. Intrarenal ROS and Ang II concentrations were also increased in HFD mice. Remarkably, these changes paralleled the augmentation uAGT excretion (3.66 ± 0.50 vs. 0.92 ± 0.13 ng/mg by week 29; P < 0.01), which occurred in the absence of overt albuminuria.. In HFD-induced T2D mice, increases in uAGT occur in the absence of overt renal injury, indicating that this biomarker accurately detects early intrarenal RAS activation.

Topics: Albuminuria; Angiotensinogen; Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Hypertension; Male; Mice; Mice, Inbred C57BL; Obesity; Renin-Angiotensin System

This study aimed to investigate the effect of combination of high-salt intake and hypertension on renal functional and histological damage, associated with renal (pro)renin receptor [(P)RR] and AT1 receptor in rats.. Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received regular rat chow (normal-salt diet 0.9%) or high-salt rat chow (high-salt diet 8.9%) for 6 weeks from 6 to 12 weeks of age. Systolic blood pressure, serum creatinine and blood urea nitrogen (BUN) were measured. Histological analysis of the kidney was performed. Western blot analysis was performed on the expressions of (P)RR, angiotensinogen and AT1 receptor in the kidney.. High-salt intake significantly increased systolic blood pressure in WKYs and especially in SHRs. High-salt intake significantly increased serum creatinine and BUN, and accelerated renal tubulointerstitial fibrosis and glomerular sclerosis in SHRs. High-salt intake significantly enhanced the renal tissue expressions of (P)RR, angiotensinogen and AT1 receptor in SHRs.. High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (P)RR and AT1 receptors in SHRs.

Topics: Angiotensinogen; Animals; Blood Pressure; Blood Urea Nitrogen; Body Weight; Creatinine; Fibrosis; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prorenin Receptor; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Signal Transduction; Sodium Chloride, Dietary; Systole

To investigate the association of genetic variants of renin angiotensin aldosterone system, endothelial nitric oxide synthase and 11-beta-hydroxylase genes, and the drug efficacy of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker.. This two time-point study was conducted from April to November 2016 at Allied Hospital, Faisalabad and National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, and comprised of hypertensive patients taking angiotensin-converting enzyme inhibitor and angiotensin receptor blocker who were followed up for 12 weeks. Baseline and follow-up clinical and biochemical parameters were measured for all patients. Total 11 polymorphisms were genotyped by polymerase chain reaction, polymerase chain reaction-restriction fragment length polymorphism and amplification-refractory mutation system-polymerase chain reaction assays. Data was divided into baseline and follow-up groups, while the latter group was further divided into responding and non-responding subgroups on the basis of patient response to angiotensin-converting enzyme inhibitor and angiotensin receptor blocker drugs. Data was analysed using SPSS 20.. Of the 45 patients, 25(55.5%) were females and 20(44.5%) were males. There was a significant reduction in the systolic blood pressure (p=0.004) and low-density lipoprotein cholesterol (p<0.001) from the baseline to the follow-up. Systolic blood pressure was significantly reduced in the responding group (p=0.003), while diastolic blood pressure (p=0.121) was not significantly different. There was no effect of angiotensin-converting enzyme, angiotensinogen, 11-beta-hydroxylase, aldosterone synthase and endothelial nitric oxide synthase gene polymorphisms on angiotensin converting enzyme inhibitor and angiotensin receptor blocker efficacy.. Inter-individual response to angiotensin converting enzyme inhibitor and angiotensin receptor blocker was found to be independent of genetic polymorphisms in renin angiotensin aldosterone system, endothelial nitric oxide synthase and 11-beta-hydroxylase genes.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cytochrome P450 Family 11; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Nitric Oxide Synthase Type III; Pakistan; Peptidyl-Dipeptidase A; Pharmacogenomic Testing; Pharmacogenomic Variants; Treatment Outcome

Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. Approach and Results: Hepatocyte-specific angiotensinogen deficient (hepAGT. Replacement of L11 and Y12 to V11 and I12, respectively, in mouse angiotensinogen does not affect renin cleavage, blood pressure, and atherosclerosis in LDL receptor-deficient mice.

Topics: Amino Acid Substitution; Angiotensin II; Angiotensinogen; Animals; Atherosclerosis; Blood Pressure; Disease Models, Animal; Female; Hepatocytes; Humans; Hypertension; Male; Mice, Knockout; Plaque, Atherosclerotic; Receptors, LDL; Renin; Species Specificity

Objective The intrarenal renin-angiotensin system (RAS) is activated in chronic kidney disease (CKD) patients and is not suppressed at night in CKD patients showing nocturnal hypertension, contributing to renal damage. Furthermore, changes in RAS inhibitor administration from morning to evening, namely chronotherapy, ameliorates renal damage at night. We attempted to clarify whether or not chronotherapy ameliorates renal damage by suppressing the intrarenal RAS activity. Methods We recruited 34 CKD patients with RAS inhibitors in the morning. We conducted ambulatory blood pressure (BP) monitoring and urine collection and evaluated urinary albumin (Alb) and angiotensinogen (AGT), which are surrogate markers for intrarenal RAS activity during the day and at night, respectively. The same experiments were conducted after changing the administration time. The ratio of values associated with morning versus evening dosing was defined as the morning to evening (M/E) ratio. Results The M/E ratio of urinary Alb had a significant and positive relationship with that of urinary AGT during the day and at night in all CKD patients. However, no significant relationships were found between the M/E ratios of urinary Alb and AGT using multiple linear regression analyses. Conversely, there was a significant and positive relationship between the M/E ratios of urinary Alb and AGT at night but not during the day in CKD patients whose estimated glomerular filtration rate was <45 mL/min/1.73 m

Topics: Adult; Albuminuria; Angiotensinogen; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Drug Chronotherapy; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Regression Analysis; Renal Insufficiency; Renal Insufficiency, Chronic; Renin-Angiotensin System

The renin-angiotensin system (RAS) is important in the onset and course of cardiovascular, kidney, and metabolic disorders. Previous reports showed that the RAS blockade protects organs and suppress the development of type 2 diabetes mellitus. A novel component of the RAS, namely, chromosome 9 open reading frame 3 (C9orf3), was recently identified, however, its effects are unclear. We evaluated whether the genetic variant of C9orf3 is associated with morbidity of hypertension among subjects with type 2 diabetes. We enrolled 382 subjects with type 2 diabetes, 222 of whom were diagnosed with hypertension. Human leukocyte genomic DNA was isolated and a genetic variant was analyzed for a C/T variant of C9orf3 (rs4385527) via PCR analysis. The relationship between the genotype and hypertension morbidity among subjects with diabetes was examined. The proportion of the respective C9orf3 genetic variants were as follows 247 CC, 119 CT, and 16 TT. The risk of hypertension was determined to be 1.58, with a 95% confidence interval of 1.11-2.27. Moreover, the p value was 0.012 for allelic comparison and for Armitage's trend test, with the C allele identified as the risk factor. Consequently, hypertension was markedly associated with type 2 diabetes in subjects with the C9orf3 variant, exhibiting a nearly 1.6-fold increased risk. The C variant of a new component of the RAS, C9orf3 (rs4385527) might have a considerable impact on the pathogenesis of hypertension in diabetes.

Topics: Alleles; Aminopeptidases; Angiotensinogen; Blood Pressure; Cohort Studies; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Angiotensin II (Ang II: a truncated octapeptide of angiotensinogen, AGT) and 11-β-hydroxylase influence regulation of blood pressure. Dysregulation of Ang II and 11-β-hydroxylase can lead to hypertension and elevate aldosterone levels. Polymorphisms in AGT (encodes AGT) and CYP11B1 (encodes 11-β-hydroxylase) shift the paradigm from physiological to pathological. Currently, various high-throughput techniques are used to genotype these polymorphisms. These techniques require expensive infrastructure and reagents. However, in developing countries, where cost is the main limiting factor, it is not feasible to use expensive techniques. So, the aim of current study was to develop efficient low-cost method for genotyping of cardiovascular disease and hypertension associated polymorphisms of AGT (rs4762, rs5051) and CYP11B1 (rs6410). For this, tetra amplification-refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method was developed and optimized for aforementioned AGT and CYP11B1 gene polymorphisms. Efficiency of T-ARMS-PCR was tested by genotyping 776 human samples. These T-ARMS-PCR assays were also validated by Sanger DNA sequencing, where 100% concordance was found, allowing the efficient use of these T-ARMS-PCR assays for polymorphism genotyping in AGT and CYP11B1 in resource limited settings. T-ARMS-PCR is low-cost, efficient and reliable assay for genotyping of AGT and CYP11B1 gene polymorphisms.

Topics: Alleles; Angiotensin II; Angiotensinogen; Blood Pressure; Cardiovascular Diseases; Female; Gene Frequency; Genotype; Genotyping Techniques; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Steroid 11-beta-Hydroxylase

The renin-angiotensin system (RAS) is a hormonal signaling mechanism implicated in the atherosclerosis and regulation of blood pressure. Angiotensin-converting enzyme (ACE) a key enzyme in the RAS, plays important roles in vascular remodeling atherosclerosis, and ischemic stroke. The aim of this study was to examine the possible contribution of the I/D in the ACE gene, M235T and T174M in the angiotensinogen (AGT) gene polymorphisms with ischemic stroke in young Mexican population.. A total of 224 patients with diagnosis of idiopathic ischemic stroke ≤45 years of age, and 224 controls matched by age and gender, were recruited from 2006 and 2016. The I/D, M235T and T174M polymorphisms were determined in all participants by PCR-RFLP.. There was a significant difference in the M235T genotype distribution (p = 0.01) and allele frequency between two groups (p = 0.01). Also, we found a significant difference in the T174M genotype distribution (p = 0.01) and the allele frequency between groups; (p = 0.02). In contrast, in I/D polymorphism, there was a similar genotype distribution; (p = 0.20) and allele distribution (p = 0.20). There were independent factors for ischemic stroke: M235T and T174M polymorphisms, smoking, hypertension, and familial history of atherothrombotic disease. The AGT levels were increased in the group of patients with stroke compared with the control group, but the AGT levels were not influenced by the allele or genotype in each polymorphism.. The M235T and T174M polymorphisms represented an increased risk for stroke in young Mexican individuals. In contrast, the I/D was not associated with in the same group of patients. The AGT levels were higher in the acute phase of stroke, but it was not determined by the polymorphisms.

Topics: Adult; Alleles; Angiotensinogen; Blood Pressure; Brain Ischemia; Case-Control Studies; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Mexico; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Renin-Angiotensin System; Risk Factors; Stroke

Herein, we studied the effects of the novel nonsteroidal selective mineralocorticoid receptor (MR) blocker, esaxerenone, on blood pressure and renal injury in Dahl salt-sensitive (DSS) rats. We also monitored intact urinary and total angiotensinogen (AGT). DSS rats were given a normal salt diet (NS: 0.4% NaCl, n = 10), a high-salt diet (HS: 8% NaCl, n = 10), HS + esaxerenone (1 mg/kg/day, p.o., n = 10), or HS + losartan (angiotensin II receptor blocker, 10 mg/kg/day, p.o., n = 10) for 6 weeks. Glomerular and tubulointerstitial tissues were obtained via a laser capture method. HS-treated DSS rats developed hypertension, albuminuria, and glomerular injury, which were associated with increased glomerular desmin staining and reduced mRNA levels of glomerular podocin and nephrin. HS-treated DSS rats also showed tubulointerstitial fibrosis with an increase in renal oxidative stress (4-hydroxynonenal staining). The urinary ((total AGT-intact AGT)/intact AGT) ratio, an indicator of intrarenal renin activity, was significantly suppressed in HS-treated DSS rats. Treatment with esaxerenone significantly decreased blood pressure, while losartan did not. Furthermore, esaxerenone attenuated the development of albuminuria, glomerular injury, and tubulointerstitial fibrosis more than losartan did, and this effect was associated with reduced renal oxidative stress. These data indicate that esaxerenone has antihypertensive and renal protective effects in salt-dependent hypertensive mice with suppressed intrarenal renin activity, as indicated by low levels of the urinary (total AGT-intact AGT)/intact AGT ratio.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Hypertension; Kidney Function Tests; Losartan; Male; Mineralocorticoid Receptor Antagonists; Pyrroles; Rats; Rats, Inbred Dahl; Renin; Sodium Chloride, Dietary; Sulfones

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; beta Catenin; Blood Pressure; Blood Urea Nitrogen; Bridged Bicyclo Compounds, Heterocyclic; Collagen Type I; Creatinine; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Fibronectins; Gene Expression Regulation; Hypertension; Kidney; Male; Nephrectomy; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Pyrimidinones; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Wnt Proteins; Wnt Signaling Pathway

Topics: Angiotensinogen; Animals; Blood Pressure; Cells, Cultured; Collagen Type IV; Disease Models, Animal; Fibrosis; Hepatocytes; Humans; Hypertension; Kidney; Lymphokines; Male; Mice; Mice, Knockout; Platelet-Derived Growth Factor; Primary Cell Culture; Up-Regulation; Ureter

Topics: Angiotensinogen; Animals; Canagliflozin; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucose; Hypertension; Kidney; Mice; Sodium

Hypertension and renal injury are common complications of type 2 diabetes mellitus (T2DM). Hyperglycemia stimulates renal proximal tubular angiotensinogen (AGT) expression via elevated oxidative stress contributing to the development of high blood pressure and diabetic nephropathy. The sodium glucose cotransporter 2 (SGLT2) in proximal tubules is responsible for the majority of glucose reabsorption by renal tubules. We tested the hypothesis that SGLT2 inhibition with canagliflozin (CANA) prevents intrarenal AGT augmentation and ameliorates kidney injury and hypertension in T2DM.. We induced T2DM in New Zealand obese mice with a high fat diet (DM, 30% fat) with control mice receiving regular fat diet (ND, 4% fat). When DM mice exhibited > 350 mg/dL blood glucose levels, both DM- and ND-fed mice were treated with 10 mg/kg/day CANA or vehicle by oral gavage for 6 weeks. We evaluated intrarenal AGT, blood pressure, and the development of kidney injury.. Systolic blood pressure in DM mice (133.9 ± 2.0 mm Hg) was normalized by CANA (113.9 ± 4.0 mm Hg). CANA treatment ameliorated hyperglycemia-associated augmentation of renal AGT mRNA (148 ± 21 copies/ng RNA in DM, and 90 ± 16 copies/ng RNA in DM + CANA) and protein levels as well as elevation of urinary 8-isoprostane levels. Tubular fibrosis in DM mice (3.4 ± 0.9-fold, fibrotic score, ratio to ND) was suppressed by CANA (0.9 ± 0.3-fold). Furthermore, CANA attenuated DM associated increased macrophage infiltration and cell proliferation in kidneys of DM mice.. CANA prevents intrarenal AGT upregulation and oxidative stress and which may mitigate high blood pressure, renal tubular fibrosis, and renal inflammation in T2DM.

Topics: Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Canagliflozin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, High-Fat; Fibrosis; Humans; Hypertension; Kidney Tubules, Proximal; Mice; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Up-Regulation

Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (-68±4 mm Hg), followed by captopril+valsartan (-54±4 mm Hg), captopril (-23±2 mm Hg), siRNA (-14±2 mm Hg), and valsartan (-10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K

Topics: Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Gene Expression Regulation; Hypertension; Injections, Subcutaneous; Liver; Male; Rats; Rats, Inbred SHR; RNA; RNA, Small Interfering

Angiotensinogen mediates an important role in the pathophysiology of preeclampsia, a disorder of pregnancy characterized by hypertension and proteinuria usually after 20 weeks of gestation. Angiotensinogen is found in two distinct posttranslational forms in the plasma, an oxidized and a reduced (free thiol) form. Higher levels of the oxidized form are associated with an increased risk of preeclampsia. We have developed novel ELISA assays to quantitate the levels of total and free thiol angiotensinogen allowing for calculation of the amount of oxidized angiotensinogen species. We describe the methodology for performing these assays.

Topics: Angiotensinogen; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Oxidation-Reduction; Pre-Eclampsia; Pregnancy; Prognosis

Topics: Adipose Tissue; Angiotensinogen; Animals; Aorta; Arterial Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Cytochrome P-450 CYP1A1; Enzyme Induction; Hypertension; Male; Mice, Inbred C57BL; Mice, Knockout; Polychlorinated Dibenzodioxins; Time Factors; Vasoconstriction; Vasodilation

Inflammation, intrarenal renin-angiotensin system (RAS) activation, oxidative stress, and carbonyl stress have been postulated to play a fundamental role in controlling blood pressure. However, little is known about the association among renal RAS activation, carbonyl stress, and blood pressure elevation.. We evaluated the relationship between blood pressure elevation and either renal RAS activity or carbonyl stress in the general population (N = 355) in Japan. To minimize the effect of antihypertensive drug therapy, we divided participants into 3 groups (normotensive, hypertensive-with-non-medication, and hypertensive-with-medication). Intrarenal RAS activity and carbonyl stress were indicated by the urinary angiotensinogen (AGT) and carbonyl compound excretion levels, respectively.. The urinary AGT and carbonyl compound excretion levels were significantly associated with blood pressure. Using a stepwise multiple regression analysis, we found that the urinary AGT excretion levels were strongly associated with blood pressure elevation, compared with inflammation, oxidative stress, and carbonyl stress markers, in all groups. Urinary carbonyl compound excretion was significantly associated with blood pressure in only the hypertensive-without-medication group. Furthermore, blood pressure was significantly increased in these participants, and both the urinary AGT and carbonyl compound levels were high. The urinary AGT excretion levels were strongly associated with elevated blood pressure in normotensive people, and inappropriate renal RAS activity and carbonyl stress independently contributed to the development of hypertension.. These findings suggest that RAS activation, particularly renal RAS activation exert a fundamental role in the pathogenesis of hypertension in the general population.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Antihypertensive Agents; Biomarkers; Blood Pressure; Case-Control Studies; Cross-Sectional Studies; Female; Humans; Hypertension; Japan; Kidney; Male; Middle Aged; Protein Carbonylation; Renal Elimination; Renin-Angiotensin System; Risk Factors; Up-Regulation

Hypertension may result from high-fat (HF) diet induced-obesity and overexposure to glucocorticoids in utero. Recent studies demonstrated the potent contribution of adipose tissue's renin-angiotensin system (RAS) to systemic RAS, which plays a key role in regulating blood pressure (BP). In this study, we investigated the effects of prenatal dexamethasone (DEX) exposure and postnatal HF diet on RAS of adipose tissue.. RAS and BP of 6-month old rats exposed to prenatal DEX and/or postnatal HF diet were examined.. Prenatal DEX plus postnatal HF exerted a synergistic effect on systolic BP. Prenatal DEX exposure suppressed plasma angiotensin (ANG) I and ANG II, whereas postnatal HF suppressed plasma ANG-(1-7) level. Prenatal DEX increased prorenin receptor and renin levels, but suppressed angiotensinogen (AGT) and angiotensin-converting-enzyme 1 (ACE1) mRNA expressions in adipose tissue. Postnatal HF increased AGT mRNA expression, but suppressed prorenin receptor, renin, ACE2, ANG II type 2 receptor (AT2R), and Mas receptor (MasR) mRNA expression levels.. Prenatal GC exposure altered the ACE1/ANG II/ANG II type 1 receptor (AT1R) axis, whereas postnatal HF negatively impacted the ACE2/ANG-(1-7)/MasR axis. Prenatal DEX exposure and postnatal HF synergistically elevated BP through a distinct programming mechanism of systemic and adipose RAS. Adipose RAS might be a target for precise hypertension treatment.

Topics: Adipose Tissue; Angiotensinogen; Animals; Blood Pressure; Dexamethasone; Diet, High-Fat; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; Hypertension; Peptidyl-Dipeptidase A; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Mas; Rats; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR.

Topics: Angiotensinogen; Animals; Blood Pressure; Cadherins; Cell Dedifferentiation; Cell Proliferation; Cells, Cultured; Complement C3; Disease Models, Animal; Genetic Predisposition to Disease; Hypertension; Kidney; Kruppel-Like Transcription Factors; Liver X Receptors; Male; Phenotype; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Transgenic; Renin; Renin-Angiotensin System; Signal Transduction; Sodium Chloride, Dietary

Clinical studies indicate that salt-sensitive hypertension is more prevalent in women than in men. However, animal models of salt sensitivity have primarily focused on the mechanisms of salt sensitivity in male animals; therefore, elucidation of these mechanisms in female animal models is needed. We have previously shown that female Balb/C mice have higher aldosterone synthase expression and aldosterone production than males. We hypothesized that female Balb/C mice develop salt-sensitive increases in blood pressure. Seven-day feeding of a 4% NaCl high-salt (HS) diet increased blood pressure in female mice without altering blood pressure in males. Females on an HS diet displayed no apparent increases in sodium retention as assessed by 24-hour urine collection, sodium balance measure, and saline loading excretion analysis. Females on an HS diet exhibited lower renin-angiotensin system activity (plasma Ang II [angiotensin II], plasma renin activity, and ACE [angiotensin-converting enzyme] activity) compared with males but developed a salt-induced elevation in adrenal aldosterone synthase expression and retained higher aldosterone levels than males on HS. This resulted in a higher aldosterone/plasma renin activity ratio in females compared with males on HS feeding. Adrenal mRNA expression of angiotensinogen and leptin receptor was increased in female mice on an HS diet. HS impaired endothelium-dependent relaxation in female mice only. MR (mineralocorticoid receptor) inhibition (eplerenone) restored blood pressure and endothelial function in females on an HS diet. Collectively, these data indicate that Balb/C mice develop sex-discrepant salt-sensitive hypertension likely via aldosterone-MR-mediated mechanisms involving impaired endothelium-dependent relaxation in females only. This study presents the first model of spontaneous sex-specific salt sensitivity, which mimics the human pathology.

Topics: Adrenal Glands; Aldosterone; Angiotensinogen; Animals; Blood Pressure; Female; Hypertension; Male; Mice; Mice, Inbred BALB C; Receptors, Leptin; Renin-Angiotensin System; Sex Factors; Sodium Chloride, Dietary

Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.

Topics: Amides; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Blood-Brain Barrier; Brain; Desoxycorticosterone Acetate; Disease Models, Animal; Fumarates; Hypertension; Mice; Mice, Knockout; Random Allocation; Rats; Rats, Inbred SHR; Reference Values; Renin-Angiotensin System

Single nucleotide polymorphisms (SNPs) in the human angiotensinogen (hAGT) gene may modulate its transcription and affect the regulation of blood pressure via activation of the renin-angiotensin aldosterone system (RAAS). In this regard, we have identified polymorphisms in the 2.5 Kb promoter of the hAGT gene that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C & -1178G/A). hAGT gene with Hap -6A/-217A (Hap I) is associated with increased blood pressure whereas, Hap -6G/-217G (Hap II) is associated with normal blood pressure in human subjects. Since RAAS over activity contributes to hypertension in obesity, we have made transgenic mice (TG) containing either Hap I or Hap II of the hAGT gene to understand the role of obesity on its transcriptional regulation. Although, a high-fat diet (60% Kcal from fat, 12 weeks) elevates hAGT and mAGT regardless of haplotype, this effect is significantly (p<0.05) accentuated in Hap I mice, in both adipose and liver tissues. Chromatin Immuno- precipitation (ChIP) assay shows an increased binding of transcription factors including, GR, CEBPβ and STAT3 to the chromatin of the Hap I TG mice after high-fat diet as compared to Hap II TG mice (p<0.05). Differential plasma levels of hAGT in Hap II and I mice, after high-fat diet, further corroborate the variable transcriptional regulation of the hAGT, governed by gene-haplotypes. Taken together, our results show that SNPs in the Hap-I of the hAGT gene promote high-fat diet-induced binding of transcription factors GR, CEBP-β and STAT3, which lead to elevated expression of the hAGT gene in hepatic and adipose tissues.

Topics: Angiotensinogen; Diet, High-Fat; Gene Expression Regulation; Gene Regulatory Networks; Haplotypes; Humans; Hypertension; Transcription, Genetic

Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis).. We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (. SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.

Topics: Angiotensinogen; Blood Pressure; Cytochrome P-450 CYP11B2; Epistasis, Genetic; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Pedigree; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Sex Factors; Young Adult

Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N-acetylgalactosamine-conjugated AGT ASO that targets the liver were compared with captopril and losartan. Spontaneously hypertensive rats fed an 8% NaCl diet, a model of malignant hypertension resistant to standard RAAS inhibitors, demonstrated robust and durable blood pressure reductions with AGT ASO treatments, which was not observed with standard RAAS blockade. Studies in rat models of acute kidney injury produced by salt deprivation revealed kidney injury with ASO treatment that reduced kidney-expressed AGT, but not in animals treated with the N-acetylgalactosamine AGT ASO despite comparable plasma AGT reductions. Administration of either captopril or losartan also produced acute kidney injury during salt deprivation. Thus, intrarenal RAAS derived from kidney AGT, and inhibited by the standard of care, contributes to the maintenance of renal function during severe RAAS challenge. Such improvements in efficacy and tolerability by a liver-selective AGT inhibitor could be desirable in individuals not at their blood pressure goal with existing RAAS blockade.

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Resistance; Hypertension; Kidney; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Treatment Outcome

Epidemiological studies have demonstrated the influence of environmental factors on HBP in the population of Lithuanian children, although the role of genetic factors in hypertension has not yet been studied. The aim of this study was to assess the distribution of AGTR1, AGT, and ACE genotypes in the Lithuanian child population and to determine whether these genotypes have an impact on HBP in childhood.. This cross-sectional study enrolled 709 participants aged 12-15 years. The subjects were genotyped for AGT (M235 T, rs699), AGTR1 (A1166C, rs5186), and ACE (rs4340) gene polymorphisms using real-time and conventional polymerase chain reactions. Blood pressure and anthropometric parameters were measured.. The prevalence of HBP was 38.6% and was more frequently detected in boys than in girls (47.9% vs. 29.5%; p < 0.001). No significant differences in the frequencies of the AGT or AGTR1 genotypes or alleles between boys and girls were observed, except for ACE genotypes. The mean SBP value was higher in HBP subjects with ACE ID genotype compared to those with ACE II homozygotes (p = 0.04). No significant differences in BP between different AGT and AGTR1 genotype groups were found. Boys who carried the ACE ID + DD genotypes had higher odds of having HBP than carriers of the ACE II genotype did (controlling for the body mass index (BMI): OR. The evaluated polymorphisms of the AGT and AGTR1 genes did not contribute to the presence of HBP in the present study and may be seen as predisposing factors, while ACE ID genotypes were associated with significantly increased odds for the development of HBP in the Lithuanian child and adolescent population - especially in boys.

Topics: Adolescent; Alleles; Angiotensinogen; Blood Pressure; Body Mass Index; Child; Cross-Sectional Studies; Female; Genotyping Techniques; Humans; Hypertension; Lithuania; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Sequence Analysis, DNA; Waist Circumference

Topics: Angiotensinogen; Animals; Blood Pressure; Caloric Restriction; Creatinine; Denervation; Female; Fetal Growth Retardation; Hypertension; Kidney; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Sympathetic Nervous System

The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.. To identify SNVs that have functional and potentially damaging effects on the renin-angiotensinogen complex and to use computational approaches to investigate how SNVs might have damaging effects.. A comprehensive set of all known SNVs in the renin and angiotensinogen proteins was extracted from the HUMA database. This dataset was filtered by removing synonymous and missense variants and using the VAPOR pipeline to predict which variants were likely to be deleterious. Variants in the filtered dataset were modeled into the renin-angiotensinogen complex using MODELLER and subjected to molecular dynamics simulations using GROMACS. The residue interaction networks of the resultant trajectories were analyzed using graph theory.. This research identified important SNVs in the interface of RAS and showed how they might affect the function of the proteins. For instance, the mutant complex containing the variant P40L in angiotensinogen caused instability in the complex, indicating that this mutation plays an important role in disrupting the interaction between renin and angiotensinogen. The mutant complex containing the SNV A188V in renin was shown to have significantly increased fluctuation in the residue interaction networks. D104N in renin, associated with renal tubular dysgenesis, caused increased rigidity in the protein complex comparison to the wild type, which probably in turn negatively affects the function of RAS.

Topics: Angiotensinogen; Blood Pressure; DNA; DNA Mutational Analysis; Genetic Variation; Humans; Hypertension; Mutation; Renin; Renin-Angiotensin System; Sequence Homology

Local renin-angiotensin system (RAS) activity in the kidneys is a pathogenetic factor in patients with primary hypertension. This study aimed to determine the relationship between local kidney RAS activity and blood pressure variability, as the literature currently lacks any such study. The study included 73 consecutive primary hypertensive patients. All patients underwent 24-h ambulatory blood pressure monitoring to determine the average real variability (ARV) index, as an indicator of blood pressure variability. Local RAS activity was determined using the urine angiotensinogen/creatinine (UAGT/UCre) ratio. The high UAGT/UCre ratio group had significantly higher mean 24-h systolic ARV than the low UAGT/UCre ratio group (13.2±3.4 vs 11.0±2.6, P=0.003). Similarly, the high UAGT/UCre ratio group had significantly higher mean 24-h diastolic ARV than the low UAGT/UCre ratio group (10.8±3.2 vs 8.7±2.2, P=0.001). Multivariate regression analysis showed that Log(UAGT/UCre) was an independent predictor of both 24-h diastolic ARV and 24-h systolic ARV. Local RAS activity in the kidneys might have a role in blood pressure variability. On the basis of these findings, we think that additional prospective studies are needed to more fully discern the effect of local RAS activity on blood pressure variability.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Creatinine; Cross-Sectional Studies; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Renin-Angiotensin System

To assess the synergistic effects of gene polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on essential hypertension (EH) in Kazakhs in Xinjiang.. A cross-sectional case-control association study was conducted in 52 1 hypertensive and 623 normotensive subjects of Kazakh ethnicity on eight common single nucleotide polymorphisms (SNPs) interspersed over five genes of the RAAS. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Interactions among the SNPs were analyzed by the multifactor dimensionality reduction method (MDR).. In single-locus analysis, subjects with AGT -6G, ACE D, and CYP11B2 -344C had increased susceptibility to EH (OR: 1.249; 1.425; 1.201). When subgrouped by sex, males with the t allele of REN Taq I had decreased risk for EH (OR: 0.529), and those with AGT -6G and CYP11B2 -344 C had increased risk for EH (OR: 1.498; 1.449). In females, carrying ACE D increased the risk for EH. (OR: 1.327). In six AGT haplotypes, H1 was protective, while H3 increased susceptibility to EH (OR: 0.683; 2.025). Interaction analysis by MDR showed that there was a strong synergistic effect between ACE I/D and CY11B2 (T-344C) and a moderate interaction between both ACE I/D and CY11B2 T-344C and AGT A-6G.. There was a strong synergistic effect between ACE I/D and CY11B2 T-344C and a moderate effect between both ACE I/D and CY11B2 T-344C and AGT A-6G. AGT -6G, ACE D, and CY11B2 -344C increased susceptibility to EH. REN Taq I, AGT -6G, CY11B2 -344 C and ACE D were associated with male and female EH, respectively. H1 and H3 of AGT were protective and risk haplotypes, respectively.

Topics: Adult; Alleles; Angiotensinogen; Blood Pressure; China; Cross-Sectional Studies; Cytochrome P-450 CYP11B2; Essential Hypertension; Ethnicity; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Protective Factors; Renin-Angiotensin System

This study determined whether angiotensinogen (AGT) has angiotensin II-independent effects using multiple genetic and pharmacological manipulations.. All study mice were in low-density lipoprotein receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor -/- mice. In mice with established adiposity, administration of AGT antisense oligonucleotide versus aliskiren led to equivalent reductions of systolic blood pressure and atherosclerosis. AGT antisense oligonucleotide administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat, and human revealed 4 highly conserved sequences within the des(angiotensin I)AGT domain. des(angiotensin I)AGT, through adeno-associated viral infection in hepatocyte-specific AGT-deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis.. AGT contributes to body weight gain and liver steatosis through functions of the des(angiotensin I)AGT domain, which are independent of angiotensin II production.

Topics: Amides; Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Atherosclerosis; Blood Pressure; Conserved Sequence; Dependovirus; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fumarates; Genetic Vectors; Genotype; Hepatocytes; Hypertension; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Oligonucleotides, Antisense; Phenotype; Protein Binding; Protein Interaction Domains and Motifs; Receptors, LDL; Renin; Signal Transduction; Time Factors; Transduction, Genetic; Weight Gain

The role of intranephron angiotensinogen (AGT) in blood pressure (BP) regulation is not fully understood. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, whereas proximal tubule-specific deletion of AGT did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP-flanked AGT alleles to achieve nephron-wide AGT disruption after doxycycline induction. Compared to controls, AGT knockout (KO) mice demonstrated markedly reduced renal AGT immunostaining, mRNA, and protein levels; unexpectedly AGT KO mice had reduced AGT mRNA levels in the liver along with 50% reduction in plasma AGT levels. BP was significantly lower in the AGT KO mice compared to controls fed a normal, low, or high Na(+) intake, with the highest BP reduction on a low Na(+) diet. Regardless of Na(+) intake, AGT KO mice had higher plasma renin concentration (PRC) and markedly reduced urinary AGT levels compared to controls. Following angiotensin-II (Ang-II) infusion, AGT KO mice demonstrated an attenuated hypertensive response despite similar suppression of PRC in the two groups. Taken together, these data suggest that nephron-derived AGT may be involved in Ang-II-dependent hypertension, however, a clear role for nephron-derived AGT in physiological BP regulation remains to be determined.

Topics: Angiotensin II; Angiotensinogen; Animals; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nephrons; Sodium, Dietary

Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice.. Control, hypertensive, hypercholesterolemic (Apoe(-/-)), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice.. Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.

Topics: Angiotensinogen; Animals; Aortic Valve; Aortic Valve Stenosis; Apolipoproteins E; Disease Models, Animal; Female; Fibrosis; Gene Expression Regulation; Hypercholesterolemia; Hypertension; Male; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; Renin; Severity of Illness Index

Lead exposure can induce increased blood pressure. Several mechanisms have been proposed to explain lead-induced hypertension. Changes in angiotensinogen (AGT) expression levels or gene variants may also influence blood pressure. In this study, we hypothesized that AGT expression levels or gene variants contribute to lead-induced hypertension. A preliminary HEK293 cell model experiment was performed to analyze the association between AGT expression and lead exposure. In a population-based study, serum AGT level was measured in both lead-exposed and control populations. To further detect the influence of AGT gene single nucleotide polymorphisms (SNPs) in lead-induced hypertension, two SNPs (rs699 and rs4762) were genotyped in a case-control study including 219 lead-exposed subjects and 393 controls. Lead exposure caused an increase in AGT expression level in HEK 293 cell models (P < 0.001) compared to lead-free cells, and individuals exposed to lead had higher systolic and diastolic blood pressure (P < 0.001). Lead-exposed individuals had higher serum AGT levels compared to controls (P < 0.001). However, no association was found between AGT gene SNPs (rs699 and rs4762) and lead exposure. Nevertheless, the change in AGT expression level may play an important role in the development of lead-induced hypertension.

Topics: Angiotensinogen; Blood Pressure; Case-Control Studies; China; Environmental Exposure; Female; Gene Expression Regulation; Genotype; Haplotypes; HEK293 Cells; Humans; Hypertension; Lead; Male; Mutagens; Polymorphism, Single Nucleotide

Intrarenal RAS has been suggested to be involved in the pathogenesis of hypertension. It was recently reported that urinary angiotensinogen excretion levels are associated with intrarenal RAS. However, few markers predicting intrarenal RAS have been investigated in obese young subjects. The present study evaluated the association between blood pressure and intrarenal RAS activity, inflammation and oxidative stress in obese young adults. Urinary angiotensinogen excretion and urinary monocyte chemotactic protein (MCP)-1, and urinary thiobarbituric acid reaction substance (TBARS) as markers of intrarenal RAS activity, inflammation, and oxidative stress, respectively, were determined from morning urine of 111 young male adults. Participants were divided into two groups based on the body mass index (BMI). Natural log-transformed urinary angiotensinogen excretion level was significantly associated with blood pressure, MCP-1 excretion, and TBARS excretion elevation in the obese group (BMI ≥25 kg/m(2)). Multivariable analyses showed that every 1 standard deviation increase in natural-log transformed urinary angiotensinogen and MCP-1 excretion, but not TBARS excretion level was associated with elevated blood pressure in the obese group. These results indicate that urinary angiotensinogen and MCP-1 excretion were associated with blood pressure elevation in this population of obese young adults. It suggested that inappropriate RAS activity and inflammation precedes hypertension in obese young subjects and urinary angiotensinogen could be a screening maker for hypertension in young obese subjects.

Topics: Adolescent; Angiotensinogen; Biomarkers; Blood Pressure; Body Mass Index; Chemokine CCL2; Female; Humans; Hypertension; Inflammation; Male; Multivariate Analysis; Obesity; Overweight; Oxidative Stress; Renin-Angiotensin System; Thiobarbituric Acid Reactive Substances; Young Adult

Long-term angiotensin II (ANG II) infusion significantly increases ANG II levels in the kidney through two major mechanisms: AT1 receptor-mediated augmentation of angiotensinogen (AGT) expression and uptake of circulating ANG II by the proximal tubules. However, it is not known whether intracellular ANG II stimulates AGT expression in the proximal tubule. In the present study, we overexpressed an intracellular cyan fluorescent ANG II fusion protein (Ad-sglt2-ECFP/ANG II) selectively in the proximal tubule of rats and mice using the sodium and glucose cotransporter 2 (sglt2) promoter. AGT mRNA and protein expression in the renal cortex and 24-h urinary AGT excretion were determined 4 wk following overexpression of ECFP/ANG II in the proximal tubule. Systolic blood pressure was significantly increased with a small antinatriuretic effect in rats and mice with proximal tubule-selective expression of ECFP/ANG II (P < 0.01). AGT mRNA and protein expression in the cortex were increased by >1.5-fold and 61 ± 16% (P < 0.05), whereas urinary AGT excretion was increased from 48.7 ± 5.7 (n = 13) to 102 ± 13.5 (n = 13) ng/24 h (P < 0.05). However, plasma AGT, renin activity, and ANG II levels remained unaltered by ECFP/ANG II. The increased AGT mRNA and protein expressions in the cortex by ECFP/ANG II were blocked in AT1a-knockout (KO) mice. Studies in cultured mouse proximal tubule cells demonstrated involvement of AT1a receptor/MAP kinases/NF-кB signaling pathways. These results indicate that intracellular ANG II stimulates AGT expression in the proximal tubules, leading to increased AGT formation and secretion into the tubular fluid, which contributes to ANG II-dependent hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Kidney Tubules, Proximal; Male; MAP Kinase Signaling System; NF-kappa B; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Sodium

Angiotensin-(1-12) [ANG-(1-12)] is processed into ANG II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human ANG-(1-12) render the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin-dependent effects of increased hAGT expression on heart function and arterial pressure. Compared with Sprague-Dawley (SD) control rats (n= 11), male homozygous TGR(hAGT)L1623 (n= 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human ANG-(1-12) immunofluorescence within myocytes of TGR(hAGT)L1623 rats was associated with a fourfold increase in cardiac ANG II content. Chymase enzymatic activity, using the rat or human ANG-(1-12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac angiotensin-converting enzyme (ACE) and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular ANG II content might be a product of an increased cardiac expression of ANG II generated through a non-renin-dependent mechanism. The data also underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function.

Topics: Angiotensinogen; Animals; Arterial Pressure; Cardiomegaly; Disease Models, Animal; Genotype; Heart Rate; Homozygote; Humans; Hydrolysis; Hypertension; Male; Myocardium; Peptide Fragments; Phenotype; Rats, Sprague-Dawley; Rats, Transgenic; Renin-Angiotensin System; Time Factors; Ultrasonography; Ventricular Function, Left

Metabolic syndrome (MetS) is associated with hypertension, obesity and dyslipidemia. Thus, genetic variants related with these conditions may modulate its development. We evaluated the effect of polymorphisms in the renin-angiotensin system (RAS) on metabolic syndrome risk in a cohort of Chilean subjects.. A total of 152 subjects, 83 with MetS (51.2 ± 9.6 years) and 69 without MetS (49.5 ± 9.3 years) of both genders were included, according to the ATP III update criteria. The rs4340 Insertion/Deletion (I/D), rs699 (T>C) and rs5186 (A>C) of the ACE, AGT and AGTR1 genes, respectively, were genotyped.. After adjusting for age and gender, we observed the DD genotype of rs4340 associated with MetS (p = 0.02). Specifically, the DD genotype was associated with MetS risk in women (OR = 4.62, 95%CI, 1.41 - 15.04; p < 0.01). In males, the AA genotype for rs5186 variant was associated with an increased risk for developing MetS when compared with women carrying the same genotype (OR = 3.2; 95%CI, 1.03 - 9.89; p = 0.04). In subjects without MetS, DD genotype was associated with increased waist circumference (p = 0.023) while subjects with MetS carrying the rs5186 TT genotype showed higher levels of HDL-cholesterol (p = 0.031).. The present study contributes data highlighting the role for RAS polymorphisms in predisposing to metabolic syndrome in Chilean subjects.

Topics: Adult; Age Factors; Aged; Angiotensinogen; Chile; Cohort Studies; Cross-Sectional Studies; Female; Gene Deletion; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sex Factors

Resistin, an adipokine involved in insulin resistance (IR) and diabetes, has recently been reported to play a role in cardiovascular events. However, its effect on blood pressure (BP) and the underlying mechanisms remain unclear. In the present study, we showed that resistin induces hypertension and IR in wild type (WT) mice, but not in tlr4(-/-) mice. Resistin upregulated angiotensinogen (Agt) expression in WT mice, whereas it had no effect on tlr4(-/-) mice, or in mice treated with the angiotensin-converting enzyme inhibitor perindopril. Real-time PCR and chromatin immunoprecipitation further confirmed that resistin activates the renin-angiotensin system (RAS) via the TLR4/P65/Agt pathway. This finding suggested an essential role of resistin in linking IR and hypertension, which may offer a novel target in clinic on the study of the association between diabetes and hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Cell Line, Tumor; Hep G2 Cells; Humans; Hypertension; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Perindopril; Renin-Angiotensin System; Resistin; Toll-Like Receptor 4; Transcription Factor RelA

Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder.. Active plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes.. The functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target.

Topics: Adolescent; Adult; Aged; Alleles; Angiotensin I; Angiotensinogen; Animals; Blood Pressure; Cell Cycle Proteins; Cell Line; Factor XIIa; Gene Expression Regulation; Genetic Loci; Genome-Wide Association Study; Genotyping Techniques; Humans; Hypertension; Juxtaglomerular Apparatus; Kallikreins; Male; Mice; Middle Aged; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Prekallikrein; Renin; Renin-Angiotensin System; Serine Endopeptidases; Transferases; Young Adult

The development of ANG II-dependent hypertension involves increased infiltration of macrophages (MΦ) and T cells into the kidney and the consequent elevation of intrarenal cytokines including IL-6, which facilitates the progression of hypertension and associated kidney injury. Intrarenal renin-angiotensin system (RAS) activation, including proximal tubular angiotensinogen (AGT) stimulation, has also been regarded as a cardinal mechanism contributing to these diseases. However, the interaction between immune cells and intrarenal RAS activation has not been fully delineated. Therefore, the present study investigated whether ANG II-treated MΦ induce AGT upregulation in renal proximal tubular cells (PTCs). MΦ were treated with 0-10(-6) M ANG II for up to 48 h. PTCs were incubated with the collected medium from MΦ. In ANG II-treated MΦ, IL-6 mRNA and protein levels were increased (1.86 ± 0.14, protein level, ratio to control); moreover, IL-6 levels were higher than TNF-α and IL-1β in culture medium isolated from ANG II-treated MΦ. Elevated AGT expression (1.69 ± 0.04, ratio to control) accompanied by phosphorylated STAT3 were observed in PTCs that received culture medium from ANG II-treated MΦ. The addition of a neutralizing IL-6 antibody to the collected medium attenuated phosphorylation of STAT3 and AGT augmentation in PTCs. Furthermore, a JAK2 inhibitor also suppressed STAT3 phosphorylation and AGT augmentation in PTCs. These results demonstrate that ANG II-induced IL-6 elevation in MΦ enhances activation of the JAK-STAT pathway and consequent AGT upregulation in PTCs, suggesting involvement of an immune response in driving intrarenal RAS activity.

Topics: Angiotensinogen; Animals; Cells, Cultured; Culture Media, Conditioned; Hypertension; Interleukin-1beta; Interleukin-6; Janus Kinases; Kidney Tubules, Proximal; Macrophages; Male; Rats; Receptor, Angiotensin, Type 1; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

The rennin-angiotensin-aldosterone system (RAAS) is a critical pathway in regulating blood pressure and salt/water homeostasis, possessing an intimate relationship with the development of systemic artery hypertension (SAH). Once hypertension is considered a risk factor for coronary artery disease (CAD), the RAAS is also related to this pathology. This investigation aimed to analyse if the frequencies of AGT M235T (rs699) and ACE I/D (rs4646994) polymorphisms are associated with CAD and SAH in African-Brazilians and Caucasian-Brazilians. In this study we analysed 714 subjects who underwent coronary angiography to detect obstructive lesions and CAD, as well as blood pressure measurement and SAH, grouped according to ethnicity: 266 African-Brazilians and 448 Caucasian-Brazilians. Among CAD and SAH cases and controls, the genotype and allele frequencies of ACE I/D polymorphism were similar in both ethnic groups. The AGT 235TT genotype and 235T allele frequencies were higher in SAH cases (32%, 54.7%) versus controls in Caucasian-Brazilians (19.8%, 46.4%; P = 0.038, P = 0.031, respectively). The AGT 235TT (OR = 1.8; P = 0.028) demonstrated to be an independent factor risk in a multivariate logistic regression increasing SAH risk in Caucasians but not in African-Brazilians. In summary, AGT M235T polymorphism was associated with SAH risk in Caucasian-Brazilians, and no association was detected with CAD. No association was also observed in ACE I/D polymorphism either in CAD or SAH in African-Brazilians and Caucasian-Brazilians.

Topics: Adult; Angiotensinogen; Black People; Brazil; Case-Control Studies; Coronary Artery Disease; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; White People

Changes in the frequencies of genotypes and mutant alleles of ACE, AGTR1, AGT, and ITGB3 genes were analyzed in patients with arterial hypertension coupled with metabolic syndrome (N=15) and compared with population data and corresponding parameters in patients with isolated hypertension (N=15). Increased frequency of genotype ID of ACE gene (hypertension predictor) was confirmed for both groups. In case of isolated hypertension, M235M genotype (gene AGT) was more frequent, in case of hypertension combined with metabolic syndrome, the frequency of genotypes A1166C and C1166C of the gene AGTR1 was higher in comparison with population data. Comparison of mutant allele frequencies in the two groups showed that at the 90% significance level allele T of the AGT gene was more frequent in hypertension coupled with metabolic syndrome (OR=1.26) and genotype A1166A of the AGTR1 gene was more frequent in the group with isolated hypertension.

Topics: Aged; Angiotensinogen; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Integrin beta3; Male; Metabolic Syndrome; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Hypertension; Kidney Tubules, Proximal; Mice; Ouabain; Peptidyl-Dipeptidase A; Phosphorylation; Protein Binding; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Transfection

Radiofrequency ablation of the renal arteries (RF-ABL) has been shown to decrease blood pressure (BP) in drug-resistant hypertensive patients who receive antihypertensive drug therapy. However, there remain questions regarding how RF-ABL influences BP independent of drug therapy and whether complete renal denervation is necessary to maximally lower BP. To study these questions, we examined the cardiovascular, sympathetic, and renal effects produced by RF-ABL of the proximal renal arteries in spontaneously hypertensive rats (SHR) with established hypertension.. SHR were instrumented (telemetry) for measurement of systolic/diastolic BP (SBP/DBP). Rats then underwent Sham-ABL or RF-ABL adjacent to the renal ostium and BP was recorded for 8 weeks. Changes in sympathetic activity, 24-hour water/sodium excretion, and levels of urinary angiotensinogen (AGT), plasma renin activity, and kidney renin content (KRC) were measured in SHR.. Compared with Sham-ABL, RF-ABL produced a sustained decrease in BP. At 8 weeks, SBP/DBP was 171±6/115±3 and 183±4/129±3mm Hg for RF-ABL and Sham-ABL SHR, respectively. Correlating with the reduction in BP, RF-ABL significantly decreased the low frequency/total and low frequency/high frequency of BP variability and attenuated the hypotensive response to chlorisondamine. Kidney norepinephrine levels were markedly decreased at 8 weeks in RF-ABL vs. Sham-ABL SHR. There were no group differences in 24-hour sodium/water excretion or urinary AGT excretion rate (6 weeks) or plasma renin activity or KRC (8 weeks). In other studies, concurrent RF-ABL plus surgical denervation initially decreased BP to a greater level than RF-ABL alone, but thereafter the reduction in BP between groups was not different.. In hypertensive SHR, bilateral RF-ABL of the proximal renal arteries produced a sustained decease in sympathetic activity and BP without changes in sodium/water excretion or activity of the systemic/renal renin-angiotensin system.

Topics: Angiotensinogen; Animals; Blood Pressure; Catheter Ablation; Disease Models, Animal; Hypertension; Kidney; Male; Natriuresis; Neural Inhibition; Norepinephrine; Rats, Inbred SHR; Rats, Inbred WKY; Renal Artery; Renin; Renin-Angiotensin System; Sympathectomy; Sympathetic Nervous System; Time Factors; Urination

To our knowledge, the relationship between simple renal cysts, hypertension and three significant genes of the renin-angiotensin system (AGT, AT1R and ACE1) has not been studied. The present study was designed to search for possible relationships between these significant polymorphic components, hypertension and simple renal cysts in Shiraz province (Iran).. A total of 160 participants were recruited from the Motahari Clinic at Shiraz University of Medical Sciences. The subjects were divided into four main groups. Detection of the ACE1 genotype was performed with a nested-polymerase chain reaction (PCR) protocol. Two separate restriction fragment length polymorphism-PCR assays were used to identify AGT and AT1R genotypes.. The allele frequency of AGT M235T differed significantly between group 1 (patients with simple renal cysts and hypertension) and normal individuals (p < 0.05). There were no significant differences in frequency for the other genes (ACE1 and AT1R).. Our findings show a relationship between the AGT-TT genotype and hypertension in patients with both hypertension and simple renal cysts. This finding suggests an additive role for the AGT gene of the renin-angiotensin system in the process of hypertension and simple renal cysts formation. Future studies are needed to elucidate the mechanisms through which this association is mediated.

Topics: Angiotensinogen; Electrophoresis, Agar Gel; Ethnicity; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Iran; Kidney Diseases, Cystic; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1

AGT is the first gene to be linked to essential hypertension (EHT). It harbors several variants of which only few polymorphisms are found to exhibit positive and negative associations with hypertension. In the present study, the AGT gene was screened to detect already reported and novel variations contributing to the development of hypertension.. In total, 215 hypertensives and 230 normotensives were screened for variations in all the five exons and a part of promoter of AGT gene using single strand conformation polymorphism analysis followed by sequencing of samples showing mobility shifts on polyacrylamide gels.. Five novel variants, namely c.-61G>A in promoter, c.-4+17C>T in intron1, c.24T>C and c.28A>T in Exon2, and c.*90 T>C in 3' untranslated region were detected in the AGT gene. c.-61G>A lies in the promoter region that plays a critical role in its expression. Variation c.-4+17C>T created a new enhancer site. c.24T>C (TCT-TCC) is a silent mutation while c.28A>T (p. M10L) has a possible damaging effect on the AGT protein. c.*90T>C, detected in the 3' untranslated region is thought to play an important role in the translation and stability of the mRNA.. Studies on the functional role of these novel variants are warranted to understand the mechanism underlying the development of EHT.

Topics: Alleles; Angiotensinogen; Essential Hypertension; Exons; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Preeclampsia is a life-threatening disorder of pregnancy. The pathogenic mechanisms of preeclampsia remain uncertain. The aim of this study is to investigate the relation between urinary angiotensinogen (UAGT) levels, an indicator of local renin-angiotensin system (RAS) activity in the kidney, and blood pressure and urinary protein excretion in preeclampsia.. For this study, 90 women aged between 20-39 years were recruited. Spot urine samples were collected to measure urinary angiotensinogen/creatinine ratio (UAGT/UCre). Log(UAGT/UCre) was compared in pregnancies with and without preeclampsia and non-pregnant controls. Factors affecting log(UAGT/UCre) in pregnancies were also investigated.. In all pregnancies log(UAGT/UCre) levels were significantly higher than in non-pregnant controls (0.58±0.19 vs. 0.33±0.14, respectively, p=0.002). However, log(UAGT/UCre) levels in pregnancies with preeclampsia were slightly lower than in normal pregnancies (0.52±0.18 vs. 0.64±0.19, respectively, p=0.012). Log(UAGT/UCre) levels were correlated positively with blood pressure and proteinuria in pregnancies with preeclampsia. However, log(UAGT/UCre) levels were not correlated with age, height, body weight, gestational age, body mass index, and serum creatinine.. This study showed that elevated local RAS activity in kidney was correlated with high blood pressure and proteinuria in preeclampsia. Local RAS activation in the kidneys may be one of the contributing factors in the development of preeclampsia.

Topics: Adult; Angiotensinogen; Blood Pressure; Creatinine; Demography; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Proteinuria; Systole; Young Adult

Urinary angiotensinogen (AGT) mainly derives from the AGT produced in proximal tubular cells. Evidence exists that supports the correlation between urinary AGT and circulating AGT.. To investigate the role of urinary AGT as a potential biomarker of intrarenal renin-angiotensin system activity in Chinese chronic kidney disease (CKD) patients.. ELISA-based method used to quantify urinary AGT. Analyzed the relationship between urinary AGT and intrarenal angiotensin II (Ang II) activity in 128 CKD patients. ELISA was applied to measure the urinary and plasma renin activity, AGT, Ang II and aldosterone. Furthermore expression levels of intrarenal renin, AGT, Ang II and Ang II receptor were examined by immunohistochemistry staining (IHCS) in 72 CKD patients undergoing renal biopsy.. The logarithmic transformation Log(urinary AGT/UCre) levels showed a normal distribution. Therefore, Log(urinary AGT/UCre) levels were used for the analyses. Average urinary AGT was 2.02 ± 0.55 ng/(mg Cr). Hypertension, urinary protein, urinary Ang II and urinary type IV collagen (Col IV) positively correlated with urinary AGT. Estimated glomerular filtration rate (eGFR), urinary sodium and serum AGT negatively correlated with urinary AGT. Multiple regression analysis indicated that low serum AGT, high urinary protein, urinary Ang II and urinary Col IV correlated significantly with high urinary AGT.. We observed positive correlation between urinary AGT and positive IHCS area of AGT, Ang II and Ang II type 1 receptor in renal tissue. These data suggest that urinary AGT might be a potential biomarker of intrarenal Ang II activity in CKD patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aldosterone; Angiotensin II; Angiotensinogen; Asian People; Biomarkers; China; Collagen Type IV; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Receptors, Angiotensin; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Young Adult

The intrarenal renin-angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. Disruption of diurnal blood pressure (BP) variation is an additional risk factor for renal damage. However, little is known regarding whether intrarenal RAS circadian rhythm exists or if it influences the disruption of diurnal BP and renal damage.. We investigated the circadian rhythm of urinary angiotensinogen (U-AGT) that reflects intrarenal RAS activity in 14 individuals without chronic kidney disease (CKD) and 36 CKD patients classified according to circadian BP rhythms.. BP values were higher during the daytime than during the nighttime in both individuals without CKD and CKD patients. U-AGT levels were not different between the daytime and nighttime in individuals without CKD, but were significantly higher in the daytime in CKD patients (log U-AGT/creatinine: daytime, 2.39 ± 0.99; nighttime, 2.24 ± 1.06; p = 0.001). Furthermore, in CKD patients showing a riser pattern of circadian BP, U-AGT levels did not decrease during the nighttime compared with those in the daytime (log U-AGT/creatinine: daytime, 2.51 ± 0.65; nighttime, 2.52 ± 0.71; p = 0.78). Circadian fluctuation of albuminuria and proteinuria occurred parallel to that of the U-AGT levels. U-AGT levels were significantly and positively correlated with the levels of BP and circadian fluctuation of U-AGT was correlated with diurnal BP changes.. These data suggest that the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which are associated with diurnal BP variation.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Blood Pressure; Case-Control Studies; Circadian Rhythm; Female; Humans; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System

Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.

Topics: Aged; Angiotensinogen; Carcinoma, Renal Cell; DNA, Neoplasm; Female; Follow-Up Studies; Gene-Environment Interaction; Humans; Hypertension; Kidney Neoplasms; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Potassium, Dietary; Prognosis; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sodium, Dietary

We investigated the association of polymorphisms in two renin-angiotensin system-related genes, expressed as angiotensinogen (AGT) and angiotensin II type 1 receptor (AGTR1), with blood lead levels and lead-related blood pressure in lead-exposed male workers in Korea. A cross-sectional study involving 808 lead-exposed male workers in Korea was conducted using a restriction fragment length polymorphism-based strategy to differentiate the various genotypes of polymorphisms in the AGT and AGTR1 genes. The association of clinical characteristics with genotypes as modifiers was estimated after adjustment for age, smoking status, drinking status, body mass index and job duration of each subject. Genotype and allele frequencies of the M235T polymorphism in AGT were associated with lead-related high blood pressure status. Moreover, blood lead levels were associated with allele frequencies of the AGT M235T polymorphism. These results suggested that the M/M genotype and M allele of AGT are risk factors for lead-related high blood pressure.

Topics: Adult; Angiotensinogen; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Lead; Male; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1

Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for the development of acute kidney injury (AKI). Although bone-marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render the BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated transgenic BMSCs (TG-BMSCs) from young end-organ-disease-free rats with increased RAS activation [human angiotensinogen/renin double transgenic rats (dTGRs)] that eventually develop hypertension and die of end-organ damage and kidney failure at 8 weeks of age. Control cells (SD-BMSCs) were isolated from wild-type Sprague-Dawley rats. Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells' therapeutic efficacy was evaluated in a rat model of acute ischaemia/reperfusion-induced AKI. Serum urea and creatinine were measured at 24 h and 48 h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation [monocyte chemoattractant protein (MCP-1), ED-1], and kidney injury [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL)]. TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast with the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by causing a shift into a pro-inflammatory phenotype with mitochondrial dysfunction.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Angiotensinogen; Animals; Cell Adhesion Molecules; Chemokine CCL2; Gene Expression Profiling; Humans; Hypertension; Immunohistochemistry; Lipocalin-2; Lipocalins; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mitochondria; Oligonucleotide Array Sequence Analysis; Oxygen Consumption; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Rats, Transgenic; Reactive Oxygen Species; Renal Insufficiency; Renin; Renin-Angiotensin System

The human angiotensinogen (hAGT) gene has polymorphisms in its 2.5-kb promoter that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, and -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C, and -1178G/A). Hap -6A/-217A is associated with human hypertension, whereas Hap -6G/-217G reduces cardiovascular risk. Hap -6A/-217A has increased promoter activity with enhanced transcription factor binding, including to the glucocorticoid receptor (GR). Glucocorticoid therapy frequently causes hypertension, the mechanisms for which are incompletely understood. We have engineered double transgenic (TG) mice containing the human renin gene with either Hap of the hAGT gene and examined the physiological significance of glucocorticoid-mediated allele-specific regulation of the hAGT gene. We have also studied the consequential effects on the renin angiotensin system and blood pressure. TG mice with Hap -6A and -6G were treated with and without a low dose of a GR agonist, dexamethasone (2.5 μg/ml), for 72 h. We found greater chromatin-GR binding with increased GR agonist-induced hAGT expression in liver and renal tissues of Hap -6A mice. Additionally, dexamethasone treatment increased circulating hAGT and angiotensin II levels in Hap -6A mice, as compared with -6G mice. Importantly, GR agonist significantly increased blood pressure and redox markers in TG mice with Hap-6A of the hAGT gene. Taken together, our results show, for the first time, that glucocorticoids affect hAGT expression in a haplotype-dependent fashion with SNPs in Hap -6A favoring agonist-induced GR binding. This leads to increased expression of the hAGT, up-regulation of the renin angiotensin system, and increased blood pressure and oxidative stress in Hap -6A mice.

Topics: Alleles; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Dexamethasone; Gene Expression; Genetic Predisposition to Disease; Glucocorticoids; Haplotypes; Humans; Hypertension; Immunoblotting; Male; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Binding; Receptors, Glucocorticoid; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase; Superoxide Dismutase-1

The renin-angiotensin system (RAS) is thought to regulate blood pressure and to be an independent risk factor for the development of left ventricular hypertrophy (LVH) and carotid intima-media thickness (CIMT). Locally produced RAS in most tissues has been recently described. It has been reported that urinary angiotensinogen levels provide a specific index of the intrarenal RAS status and is significantly correlated with blood pressure and proteinuria. The aim of this study was to evaluate the relationship of local intrarenal RAS with LVH and CIMT in hypertensive renal transplant recipients (RTRs).. A total of 96 non-diabetic RTRs (50 hypertensive patients, 46 normotensive patients) were included in this study. Urinary angiotensinogen (UAGT)/urinary creatinine (Ucre) was significantly higher in hypertensive patients compared with normotensive patients (p < 0.01). Left ventricular mass (LVM)I and CIMT were significantly higher in hypertensive patients compared with the normotensive patients (p < 0.01). Importantly, a significant positive correlation was found between UAGT/Ucre levels and LVMI (r = 0.724, p = 0.012) and also CIMT (r = 0.452, p = 0.02) in hypertensive RTRs.. These data indicate that UAGT is increased in hypertensive RTRs, and local RAS may play an important role in the development of cardiovascular abnormalities in hypertensive renal transplant recipients.

Topics: Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Carotid Intima-Media Thickness; Case-Control Studies; Creatinine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Proteinuria; Renin-Angiotensin System; Risk Factors; Transplant Recipients

We tested the controversial hypothesis that vitamin D depletion aggravates hypertension and target-organ damage by influencing renin.. Four-week-old double-transgenic rats (dTGR) with excess angiotensin (Ang) II production due to overexpression of the human renin (hREN) and angiotensinogen (hAGT) genes received vitamin D-depleted (n=18) or standard chow (n=15) for 3 weeks. The depleted group had very low serum 25-hydroxyvitamin D levels (mean±SEM; 3.8±0.29 versus 40.6±1.19 nmol/L) and had higher mean systolic BP at week 5 (158±3.5 versus 134.6±3.7 mm Hg, P<0.001), week 6 (176.6±3.3 versus 162.3±3.8 mm Hg, P<0.01), and week 7 (171.6±5.1 versus 155.9±4.3 mm Hg, P<0.05). Vitamin D depletion led to increased relative heart weights and increased serum creatinine concentrations. Furthermore, the mRNAs of natriuretic peptides, neutrophil gelatinase-associated lipocalin, hREN, and rRen were increased by vitamin D depletion. Regulatory T cells in the spleen and in the circulation were not affected. Ang metabolites, including Ang II and the counter-regulatory breakdown product Ang 1 to 7, were significantly up-regulated in the vitamin D-depleted groups, while ACE-1 and ACE-2 activities were not affected.. Short-term severe vitamin D depletion aggravated hypertension and target-organ damage in dTGR. Our data suggest that even short-term severe vitamin D deficiency may directly promote hypertension and impacts on renin-angiotensin system components that could contribute to target-organ damage. The findings add to the evidence that vitamin D deficiency could also affect human hypertension.

Topics: Acute-Phase Proteins; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Creatinine; Heart; Humans; Hypertension; Lipocalin-2; Lipocalins; Natriuretic Peptides; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System; Risk Factors; RNA, Messenger; Vitamin D; Vitamin D Deficiency

To test the hypothesis that in a high-salt induced hypertension in normal rats, whether the changes of intrarenal renin-agiotensin system (RAS) play a critical role in renal damage and could be reflected by urinary angiotensinogen (AGT).. In the study, 27 normotensive male Wistar-Kyoto rats were divided into control group [0.3% (mass faction) NaCl in chow, n=9, NS], high-salt diet group [8% (mass faction) NaCl in chow, n=9, HS] and high-salt diet with Losartan group [8% (mass faction) NaCl in chow and 20 mg/(kg×d) Losartan in gavages, n=9, HS+L)], and were fed for six weeks. The blood pressure was monitored and urine samples were collected every 2 weeks. AGTs in plasma, kidney and urine were measured by ELISA kits. The renal cortex expression of mRNA and protein of AGT were measured by Real-time PCR and immunohistochemistry (IHC). The renin activity and ANG II were measured by radioimmunoassay (RIA) kits.. Compared with NS, the systolic blood pressure (SBP) [(156 ± 2) mmHg vs. (133 ± 3) mmHg, P<0.05] increased significantly at the end of the 2nd week, and the urinary protein [(14.07 ± 2.84) mg/24 h vs. (7.62 ± 3.02) mg/24 h, P<0.05] increased significantly at the end of the 6th week in HS. Compared with HS, there was no significant difference in SBP (P>0.05) but the proteinuria [(9.69 ± 2.73) mg/24 h vs. (14.07 ± 2.84) mg/24 h, P<0.01] decreased significantly in HS+L. Compared with NS, there was no significant difference in the plasma renin activity, angiotensinogen and ANG II level in HS (P>0.05), but the renal cortex renin content [(8.72 ± 1.98) ng/(mL × h) vs. (4.37 ± 1.26) ng/(mL × h), P<0.05], AGT formation [(4.02 ± 0.60) ng/mg vs. (2.59 ± 0.42) ng/mg, P<0.01], ANG II level [(313.8 ± 48.76) pmol/L vs. (188.9 ± 46.95) pmol/L, P<0.05] were increased significantly in HS, and the urinary AGT and ANG II excretion rates increased significantly (P<0.05). Compared with HS, the plasma renin activity, angiotensinogen and ANG II level were significantly increased (P<0.05), but the renal cortex renin content, AGT formation, ANG II level significantly decreased (P<0.05), and the urinary AGT and ANG II excretion rates decreased significantly in HS+L (P<0.05). The urinary AGT excretion rates were positively correlated with the AGT level in the renal cortex (P<0.05).. Up-regulation of intarenal RAS may contribute to renal damage in high-salt induced hypertension rats. Urinary AGT may reflect the status of intrarenal RAS.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Hypertension; Kidney; Male; Proteinuria; Rats; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Up-Regulation

It has not yet been fully elucidated whether cardiac tissue levels of prorenin, renin and (P)RR are activated in hypertension with a high salt intake. We hypothesized that a high salt intake activates the cardiac tissue renin angiotensin system and prorenin-(pro)renin receptor system, and damages the heart at an early stage of hypertension.. Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) received regular (normal-salt diet, 0.9%) and high-salt (8.9%) chow for 6 weeks from 6 to 12 weeks of age. The systolic blood pressure, plasma renin activity (PRA) and plasma angiotensin II concentration were measured, and the protein expressions of prorenin, (pro)renin receptor, angiotensinogen, angiotensin II AT1 receptor, ERK1/2, TGF-β, p38MAPK and HSP27 in the myocardium were investigated. The cardiac function was assessed by echocardiography, and histological analysis of the myocardium was performed.. The high-salt diet significantly increased the systolic blood pressure, and significantly reduced the PRA and plasma angiotensin II concentration both in the WKYs and SHRs. Cardiac expressions of prorenin, renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p-p38MAPK, TGF-β and p-HSP27 were significantly increased by the high salt diet both in the WKYs and SHRs. The high-salt diet significantly increased the interventricular septum thickness and cardiomyocyte size, and accelerated cardiac interstitial and perivascular fibrosis both in the WKYs and SHRs. On the other hand, dilatation of left ventricular end-diastolic dimension and impairment of left ventricular fractional shortening was shown only in salt loaded SHRs.. The high-salt diet markedly accelerated cardiac damage through the stimulation of cardiac (P)RR and angiotensin II AT1 receptor by increasing tissue prorenin, renin and angiotensinogen and the activation of ERK1/2, TGF-β, p38MAPK and HSP27 under higher blood pressure.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Echocardiography; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Heart Ventricles; HSP27 Heat-Shock Proteins; Hypertension; Lung; Male; Myocardium; Organ Size; p38 Mitogen-Activated Protein Kinases; Prorenin Receptor; Rats; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin; Signal Transduction; Sodium Chloride, Dietary; Transforming Growth Factor beta1

Urinary excretion of angiotensinogen [urine angiotensinogen (UAGT)] has been proposed as a biomarker of intrarenal renin-angiotensin system activity. We investigated the association between UAGT and salt-sensitivity and potassium-sensitivity of blood pressure (BP) among Genetic Epidemiology Network of Salt Sensitivity study participants.. The intervention consisted of a 7-day low-sodium diet (51.3  mmol sodium/day), 7-day high-sodium diet (307.8  mmol sodium/day), and 7-day high-sodium diet with potassium supplementation (307.8  mmol sodium/day and 60  mmol potassium/day). Twenty-four-hour UAGT was estimated at baseline and at the end of each intervention for 100 randomly selected participants.. Median UAGT (μg/24  h) and UAGT-to-creatinine ratio (UAGT/Cr, μg/g) were significantly reduced during the low-sodium and potassium-supplementation interventions and increased during the high-sodium intervention (both P = 0.01). Baseline log-transformed UAGT and UAGT/Cr ratio were significantly positively associated with BP at baseline and at the end of each intervention. For example, one standard deviation higher log-UAGT/Cr ratio (1.2  μg/g) was associated with a 5.0-mmHg (95% confidence interval 2.3-7.8) higher SBP at the end of the high-sodium intervention, after adjusting for multiple covariates (P = 0.003). In addition, one standard deviation higher log-UAGT/Cr ratio was associated with a 1.6-mmHg increase in age-adjusted and sex-adjusted SBP from the low-sodium intervention to the high-sodium intervention (95% confidence interval 0.1-3.1, P = 0.04). This association was no longer statistically significant after multivariable adjustment.. These data indicate that elevated UAGT are associated with BP sodium sensitivity. Augmentation of intrarenal renin-angiotensin system activity may play an important role in developing salt-sensitive hypertension.

Topics: Adolescent; Adult; Angiotensinogen; Biomarkers; Blood Pressure; Creatinine; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Renin-Angiotensin System; Sodium Chloride, Dietary; Young Adult

Several single nucleotide polymorphisms (SNPs) of renin-angiotensin system (RAS) genes are associated with hypertension (HT) but most of them are focusing on single locus effects. Here, we introduce an unbalanced function based on multifactor dimensionality reduction (MDR) for multiloci genotypes to detect high order gene-gene (SNP-SNP) interaction in unbalanced cases and controls of HT data. Eight SNPs of three RAS genes (angiotensinogen, AGT; angiotensin-converting enzyme, ACE; angiotensin II type 1 receptor, AT 1 R) in HT and non-HT subjects were included that showed no significant genotype differences. In 2- to 6-locus models of the SNP-SNP interaction, the SNPs of AGT and ACE genes were associated with hypertension (bootstrapping odds ratio [Boot-OR] = 1.972~3.785; 95%, confidence interval (CI) 1.26~6.21; P < 0.005). In 7- and 8-locus model, SNP A1166C of AT 1 R gene is joined to improve the maximum Boot-OR values of 4.050 to 4.483; CI = 2.49 to 7.29; P < 1.63E - 08. In conclusion, the epistasis networks are identified by eight SNP-SNP interaction models. AGT, ACE, and AT 1 R genes have overall effects with susceptibility to hypertension, where the SNPs of ACE have a mainly hypertension-associated effect and show an interacting effect to SNPs of AGT and AT 1 R genes.

Topics: Aged; Angiotensinogen; Epistasis, Genetic; Female; Gene Regulatory Networks; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Both hyperuricaemia and activation of the intrarenal renin-angiotensin system (RAS) play an important role in the development of hypertension and renal damage. However, it has not been clear whether hyperuricaemia is associated with renal damage due to hypertension or intrarenal RAS activation, as well as their circadian rhythms.. We recruited 43 chronic kidney disease (CKD) patients who did not receive RAS blockers and antihyperuricaemic drugs, and investigated the relationship among serum uric acid (sUA) levels, the circadian rhythm of urinary angiotensinogen (U-AGT) excretion levels, and the levels of albuminuria (U-ACR) and proteinuria (U-P/Cr).. sUA levels were significantly associated with estimated glomerular filtration rate (eGFR) (P = 0.002), systolic blood pressure (SBP) (daytime, P = 0.031), and U-ACR (daytime, P = 0.006 and nighttime, P = 0.008) and U-P/Cr (daytime, P = 0.017 and nighttime, P = 0.013). However, there were no significant differences between sUA levels and SBP in nighttime and U-AGT excretion levels in both time periods. Multiple regression analyses for sUA levels were performed using age, sex, eGFR and each parameter (SBP, U-AGT/Cr, U-ACR or U-P/Cr). sUA levels were not associated with SBP or U-AGT/Cr in both time periods. sUA levels tended to correlate with U-P/Cr levels in nighttime, and were significantly associated with U-P/Cr in daytime (P = 0.026) and U-ACR in daytime (P = 0.017) and nighttime (P = 0.046). Moreover, no significant differences were found between sUA levels and night-to-day ratios of some parameters.. These data suggest that hyperuricaemia is associated with renal damage, independently of hypertension and intrarenal RAS activation, as well as their circadian rhythms.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensinogen; Biomarkers; Blood Pressure; Circadian Rhythm; Female; Glomerular Filtration Rate; Humans; Hypertension; Hyperuricemia; Kidney; Kidney Diseases; Linear Models; Male; Middle Aged; Multivariate Analysis; Renin-Angiotensin System; Risk Factors; Time Factors; Uric Acid; Young Adult

The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension.. Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus.. The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril.. RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Captopril; Corticosterone; Cyclic N-Oxides; Denervation; Electric Stimulation; Hypertension; Male; Oxidative Stress; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Spin Labels; Sympathetic Nervous System; Thiobarbituric Acid Reactive Substances

Topics: Angiotensinogen; Blood Pressure; Female; Humans; Hypertension; Male; Potassium; Sodium Chloride, Dietary

Angiotensinogen (AGT) has been shown to have a role in cardiac hypertrophy, while depletion of the AGT gene in spontaneously hypertensive rats (SHR) has not been investigated. The present study investigated the effect of AGT knockdown on cardiac hypertrophy in SHR. For this, small hairpin (sh)RNAs were intravenously injected into SHRs, using a nanoparticle‑mediated transfection system. The experimental rats were divided into the following groups: a) Blank control with water treatment only, b) negative control with biscarbamate‑crosslinked Gal‑polyethylene glycol polyethylenimine nanoparticles (GPE)/negative shRNA, c) AGT‑RNA interference (RNAi) group with GPE/AGT‑shRNA, and 4) normotensive control using Wistar‑Kyoto rats (WKY) with water treatment. Three and five days following the first injection, the levels of hepatic AGT mRNA and AGT protein as well as plasma levels of AGT were markedly decreased in the AGT‑RNAi group (P<0.05). Furthermore, a significant decrease in systolic blood pressure (SBP), left ventricular weight to body weight ratio and heart weight to body weight ratio were observed in the AGT‑RNAi group compared with those in the control groups. The depletion of AGT in SHR led to a reduction in SBP by 30±4 mmHg, which was retained for >10 days. Cardiac hypertrophy was also significantly improved in AGT‑knockdown rats. In conclusion, the present study showed that AGT‑silencing had a significant inhibitory effect on hypertension and hypertensive‑induced cardiac hypertrophy in SHRs.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Gene Knockdown Techniques; Genetic Therapy; Hypertension; Male; Myocardium; Nanoparticles; Organ Size; Rats, Inbred SHR; RNA Interference; RNA, Messenger; RNA, Small Interfering; Transfection; Ventricular Remodeling

The majority of CKD-related complications stem from cardiovascular pathologies such as hypertension. To help reduce cardiovascular complications, aerobic exercise is often prescribed. Emerging evidence suggests high intensity interval training (HIIT) may be more beneficial than traditional aerobic exercise. However, appraisals of varying forms of aerobic exercise, along with descriptions of mechanisms responsible for health-related improvements, are lacking. This study examined the effects of 8 weeks of HIIT (85% VO2max), versus low intensity aerobic exercise (LIT; 45-50% VO2max) and sedentary behaviour (SED), in an animal model of early-stage CKD. Tissue-specific mRNA expression of RAAS-related genes and CKD-related clinical markers were examined. Compared to SED, HIIT resulted in increased plasma albumin (p = 0.001), reduced remnant kidney weight (p = 0.028), and reduced kidney weight-body weight ratios (p = 0.045). Compared to LIT, HIIT resulted in reduced Agt mRNA expression (p = 0.035), reduced plasma LDL (p = 0.001), triglycerides (p = 0.029), and total cholesterol (p = 0.002), increased plasma albumin (p = 0.047), reduced remnant kidney weight (p = 0.005), and reduced kidney weight-body weight ratios (p = 0.048). These results suggest HIIT is a more potent regulator of several markers that describe and influence health in CKD.

Topics: Angiotensinogen; Animals; Disease Models, Animal; Exercise Therapy; Humans; Hypertension; Male; Rats; Renal Insufficiency, Chronic; RNA, Messenger; Serum Albumin; Triglycerides

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary kidney diseases that frequently result in renal failure. In this cross-sectional observational cohort study, we evaluated urinary angiotensinogen (AGT) as a potential biomarker to assess renal function in ADPKD.. Urinary AGT was measured in 233 ADPKD patients and its association with estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV) were evaluated. The localization of AGT and other renin-angiotensin system (RAS)-related molecules were identified using immunohistochemistry in human ADPKD tissues.. Baseline urinary AGT/Cr was negatively correlated with CKD-EPI eGFR (r(2) = 0.162, P < 0.001) and positively correlated with htTKV (r(2) = 0.107, P < 0.001). Both urinary AGT/Cr and plasma renin activity levels were significantly elevated in hypertensive ADPKD patients. Among hypertensive subjects, urinary AGT/Cr was significantly increased in the advanced CKD stages (III-V) compared to early CKD stages (I-II) (28.6 ± 60.3 vs. 93.2 ± 139.3 μg/g, P < 0.001). Immunohistochemical study showed strong expression of AGT along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells.. Our results suggested that urinary AGT/Cr may be a valuable biomarker for renal damage in ADPKD since intrarenal ischemic insults induced by cyst growth and subsequent intrarenal RAS activation may play a potential role in the development of hypertension and renal dysfunction in ADPKD.

Topics: Adult; Angiotensinogen; Biomarkers; Cohort Studies; Creatinine; Cross-Sectional Studies; Epithelial Cells; Female; Glomerular Filtration Rate; Humans; Hypertension; Immunohistochemistry; Kidney; Kidney Tubules; Male; Middle Aged; Organ Size; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Renin; Severity of Illness Index

We recently demonstrated that adipocyte deficiency of angiotensinogen (AGT) ablated high-fat diet-induced elevations in plasma angiotensin II (Ang II) concentrations and obesity-hypertension in male mice. Hepatocytes are the predominant source of systemic AGT. Therefore, in this study, we defined the contribution of hepatocyte-derived AGT to obesity-induced elevations in plasma AGT concentrations and hypertension. Male Agt(fl/fl) mice expressing albumin-driven Cre recombinase were bred to female Agt(fl/fl) mice to generate Agt(fl/fl) or hepatocyte AGT-deficient male mice (Agt(Alb)). Mice were fed a low-fat or high-fat diet for 16 weeks. Hepatocyte AGT deficiency had no significant effect on body weight. Plasma AGT concentrations were increased in obese Agt(fl/fl) mice. Hepatocyte AGT deficiency markedly reduced plasma AGT and Ang II concentrations in lean and obese mice. Moreover, hepatocyte AGT deficiency reduced the content and release of AGT from adipose explants. Systolic blood pressure was markedly decreased in lean (by 18 mm Hg) and obese Agt(Alb) mice (by 54 mm Hg) compared with Agt(fl/fl) controls. To define mechanisms, we quantified effects of Ang II on mRNA abundance of megalin, an AGT uptake transporter, in 3T3-L1 adipocytes. Ang II stimulated adipocyte megalin mRNA abundance and decreased media AGT concentrations. These results demonstrate that hepatocytes are the predominant source of systemic AGT in both lean and obese mice. Moreover, reductions in plasma angiotensin concentrations in obese hepatocyte AGT-deficient mice may have limited megalin-dependent uptake of AGT into adipocytes for the production of Ang II in the development of obesity-hypertension.

Topics: Angiotensinogen; Animals; Blood Pressure; Body Weight; Cells, Cultured; Disease Models, Animal; Female; Gene Expression Regulation; Hepatocytes; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; RNA, Messenger; Thinness

Exercise training (T) blunts functional deficits and renin-angiotensin system (RAS) hyperactivity in hypertensive individuals. There is no information on T-induced temporal changes of brain RAS. We evaluate now the simultaneous effects of T on functional responses and time course changes in the expression/activity of brain RAS components in autonomic cardiovascular-controlling areas.. Spontaneously hypertensive rats (SHR) and age-matched normotensive controls (WKY) were trained for 0, 1, 2, 4, 8 and 12 weeks. Sedentary (S) groups served as time-controls. After arterial pressure (AP) and heart rate (HR) recordings at rest, fresh and fixed brains were harvested for qPCR and immunofluorescence assays. SHR-S vs. WKY-S exhibited higher mean AP (MAP) and HR, increased pressure variability and sympathetic activity, elevated AT1 receptor (AT1) expression in nucleus tractus solitarii (NTS) and higher Mas receptor expression in the rostroventrolateral medulla (RVLM). In SHR, T promptly (T2 on) reduced sympathetic variability to heart/vessels and largely decreased angiotensinogen expression in the paraventricular hypothalamic nucleus (PVN) and NTS, with a late RVLM reduction (T4). AT1 expression was only reduced at T12 (PVN and NTS) with transient, not maintained Mas receptor changes in PVN and RVLM. These responses were accompanied by baseline MAP and HR reduction in the SHR-T (from T4 on). In the SHR group, PVN angiotensinogen expression correlated positively with sympathetic activity, resting MAP and HR. In WKY-T, a precocious (T2-T12) RVLM AT1 decrease preceded the appearance of resting bradycardia (from T8 on).. Early and maintained reduction of angiotensinogen content in autonomic areas of the SHR is the most prominent effect of training on brain RAS. Down-regulation of PVN RAS expression is an essential factor to drive cardiovascular benefits in SHR-T, while resting bradycardia in WKY-T is correlated to RVLM AT1 reduction.

Topics: Angiotensinogen; Animals; Autonomic Nervous System; Blood Pressure; Brain; Gene Expression Regulation; Heart Rate; Hypertension; Male; Physical Conditioning, Animal; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Time Factors

Hypertension is a serious risk factor affecting up to 30% of the world's population with a heritability of more than 30-50%. The aim of this study was to investigate the contribution of the polymorphisms localized in the angiotensinogen (AGT) gene, a main component of the renin-angiotensin-aldosterone system, in inducing the susceptibility to essential hypertension (EH) among isolated populations (Yi and Hani minorities) with low prevalence rate from the remote region of Yunnan in China.. A case-control association study was performed, and all subjects were genotyped for the seven single nucleotide polymorphisms localized in the AGT region by polymerase chain reaction-restriction fragment length polymorphism analysis.. Three polymorphisms, i.e. rs5046, rs5049, and rs2478544, were significantly associated with EH among the Hani minority. The associations, found in the Yi minority, did not reach a conclusive level of statistical significance. The polymorphisms of rs2478544 and rs5046 caused the transformations of exonic splicing enhancer sites and transcription factor binding sites, respectively, in the bioinformatic analyses. The haplotype-rs5046T, rs5049A, rs11568020G, rs3789679C, rs2478544C was susceptible for EH among the Hani minority.. Our findings suggested that the AGT polymorphisms have played a vital role in determining an individual's susceptibility to EH among the isolated population, which would be helpful for EH management in the remote mountainous region of Yunnan in China.

Topics: Alleles; Angiotensinogen; Blood Pressure; Case-Control Studies; China; Computational Biology; Diastole; Essential Hypertension; Ethnicity; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Risk Factors; Systole

The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan- and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymase-dependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension.

Topics: Albuminuria; Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Chymases; Disease Models, Animal; Diuretics; Heart Rate; Hypertension; Male; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Serine Proteinase Inhibitors; Sodium Chloride, Dietary; Time Factors

Maternal low protein diet programs offspring to develop hypertension as adults. Transient exposure to angiotensin converting enzyme inhibitors or angiotensin II receptor blockers can result in improvement in hypertension. Male rats whose mothers received a low protein diet during the last half of pregnancy were given either vehicle, continuous enalapril (CE) in their drinking water or were given transient enalapril exposure (TE) after weaning at 21 days of age. The TE group had enalapril in their drinking water for 21 days starting from day 21 of life. All rats were studied at 6 months of age. Vehicle treated rats whose mothers were fed a low protein diet were hypertensive, had albuminuria, and demonstrated upregulation of the intrarenal renin-angiotensin system as evidenced by higher urinary angiotensinogen and urinary angiotensin II levels. In low protein rats both continuous and transient exposure to enalapril normalized blood pressure, urinary angiotensinogen and urinary angiotensin II levels at 6 months of age, but only continuous administration of enalapril decreased urinary albumin excretion. These data support the importance of the intrarenal renin-angiotensin system in mediating hypertension in programmed rats and transient exposure to enalapril can reprogram the hypertension and dysregulation of the intrarenal renin-angiotensin system.

Topics: Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Enalapril; Female; Hypertension; Kidney; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Gene polymorphisms of the renin-angiotensin system are involved in the pathophysiology of hypertension. We genotyped 4 polymorphisms of angiotensinogen (AGT) gene A-20C (rs5050), A-6G (rs5051), C3889T (rs4762), and C4072T (rs699) by polymerase chain reaction-restriction fragment length polymorphism in 652 patients and 780 controls to examine the association of AGT and hypertension in a Northern Han Chinese population. There were significant differences in the distribution of genotypes and allele frequencies at C4072T between the patients and the controls (both P < .01); patients with CC genotype had a higher risk of hypertension (odds ratio = 1.7, 95% confidence interval 1.4-2.1). The distribution of genotypes at A-6G was significantly different between patients and controls (P < .05). No other significant differences in genotypes or frequencies were observed. No association was observed between the haplotypes of AGT and hypertension. The AGT-6A and 4072C alleles are associated with susceptibility to hypertension in this population.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Asian People; Essential Hypertension; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System

Topics: Angiotensinogen; Antihypertensive Agents; Blood Pressure; Drug Design; Genetic Predisposition to Disease; Heredity; Humans; Hypertension; Molecular Targeted Therapy; Pedigree; Phenotype; Polymorphism, Genetic; Risk Factors

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.. Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.. High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.. Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.

Topics: Albuminuria; Amides; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cytoprotection; Disease Models, Animal; Disease Progression; Down-Regulation; Fumarates; Humans; Hydralazine; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Ramipril; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Time Factors

Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone.. Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction.. The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

Topics: Adult; Aged; Aldosterone; Angiotensinogen; Animals; Cabergoline; Ergolines; Female; Humans; Hypertension; Iliac Artery; In Vitro Techniques; Male; Middle Aged; Pituitary ACTH Hypersecretion; Rats; Renin; Renin-Angiotensin System; Somatostatin; Vasoconstriction

Angiotensinogen (AGT) is the precursor of active vasoconstrictive octapeptide angiotensin II (Ang II) in the renin-angiotensin-aldosterone system. Blocking the AGT-converting enzymes in the pathway and the Ang II receptor through pharmacological agents has been proven to be effective in lowering blood pressure (BP) in hypertensive patients. In this study, we developed chemically modified small interfering RNAs (siRNA) to target hepatic AGT mRNA in rats. Lipid nanoparticle encapsulated siRNAs were efficiently delivered to rat liver and resulted in significant reduction in hepatic Agt mRNA levels and plasma AGT concentration without impairing liver function. Single intravenous injection of Agt siRNA led to significant and sustained BP lowering in spontaneous hypertensive rats and in Sprague-Dawley rats, and the effect was maintained by weekly siRNA dosing. Data presented here provide proof-of-feasibility for the use of siRNA technology for inhibition of peripheral AGT levels via hepatic mRNA silencing with beneficial effects on BP in preclinical rat models. Similar approach could be used for validation of novel hypertension hepatic and extrahepatic targets.

Topics: Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Hepatocytes; Hypertension; Liver; Male; Nanoparticles; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Small Interfering

Abstract Introduction: AGT gene harbors several variants of which 21 are found to be in high linkage disequilibrium as per Hapmap database. Studies delineating the importance of these tagged SNPs are very limited and lacking from Indian population. In the present study, we evaluated the contribution of four tagged SNPs namely, g.6635G > A, g.6506G > A, g.12840G > A, and g.13828T > C at AGT locus along with the analyses of haplotype and epistatic interactions in causing susceptibility to essential hypertension (EHT).. About 215 hypertensives and 230 normotensives were genotyped for selected tagged SNPs using PCR-RFLP method.. Significant association was obtained for g.6635G > A and g.6506G > A polymorphisms wherein GG homozygotes for both the markers were at risk for developing the condition. g.13828T > C polymorphism specially, female heterozygotes (TC) were found to be at increased risk for EHT. Haplotype GGGC was found to have a significant protective effect (p = 0.0059). Markers g.6506G > A and g.12840G > A resulted in the creation of new enhancer sites thereby affecting splicing process.. The present report is the first one in the literature showing general- and gender-specific association of g.6506G > A and g.13828T > C polymorphisms, respectively, with EHT. However, further studies for replication of present observations are warranted from other populations and other parts of India.

Topics: Angiotensinogen; Case-Control Studies; Essential Hypertension; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Models, Genetic; Polymorphism, Single Nucleotide; Risk Factors

Topics: Angiotensinogen; Animals; Blood Pressure; Hypertension; Liver; Male; Renin-Angiotensin System

The (pro)renin receptor ((P)RR) is expressed in several tissues including kidney, heart and brain, and is thought to regulate the tissue renin-angiotensin system (RAS) through the non-proteolytic activation of prorenin. (P)RR is cleaved by furin to generate soluble (P)RR (s(P)RR), which is secreted into the extracellular space. s(P)RR is a candidate biomarker reflecting the status of the tissue RAS. Here, we investigated the relationship between background factors and serum s(P)RR levels. We measured s(P)RR levels in 122 patients with essential hypertension (EH) and assessed the relationships between background factors and s(P)RR levels. Serum s(P)RR levels were 19.0±4.9 ng ml(-1). Single regression analyses showed that age (r=0.251, P<0.01), serum creatinine levels (r=0.229, P<0.05) and urinary angiotensinogen excretion (r=0.196, P<0.05) were positively correlated with s(P)RR levels, whereas estimated glomerular filtration rate (eGFR; r=-0.337, P<0.001) were negatively correlated. Multiple regression analyses of age, blood pressure (BP), hemoglobin A1c (HbA1c) and s(P)RR levels revealed that age and s(P)RR levels were negatively correlated with the eGFR (P<0.05). In patients with EH, serum s(P)RR levels correlated positively with renal function independent of age, BP and HbA1c. These findings support s(P)RR as a useful biomarker that reflects the status of the tissue RAS.

Topics: Adult; Age Factors; Aged; Angiotensinogen; Essential Hypertension; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Receptors, Cell Surface; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) promotes AT1R internalization along with suppression of pathological activation of tissue AT1R signaling. However, the functional significance of ATRAP in renal sodium handling and blood pressure regulation under pathological stimuli is not fully resolved. Here we show the blood pressure of mice with a gene-targeted disruption of ATRAP was comparable to that of wild-type mice at baseline. However, in ATRAP-knockout mice, angiotensin II-induced hypertension was exacerbated and the extent of positive sodium balance was increased by angiotensin II. Renal expression of the sodium-proton antiporter 3, a major sodium transporter in the proximal tubules, urinary pH, renal angiotensinogen production, and angiotensin II content was unaffected. Stimulation of the renal expression and activity of the epithelial sodium channel (ENaC), a major sodium transporter in the distal tubules, was significantly enhanced by chronic angiotensin II infusion. The circulating and urinary aldosterone levels were comparable. The blood pressure response and renal ENaC expression by aldosterone were not affected. Thus, ATRAP deficiency exacerbated angiotensin II-mediated hypertension by pathological activation of renal tubular AT1R by angiotensin II. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone-independent manner.

Topics: Adaptor Proteins, Signal Transducing; Aldosterone; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Epithelial Sodium Channels; Gene Deletion; Hydrogen-Ion Concentration; Hypertension; Kidney Tubules, Distal; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Angiotensin, Type 1; Renal Reabsorption; RNA, Messenger; Sodium; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Urinalysis; Vasoconstrictor Agents

Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small druglike molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.

Topics: Angiotensinogen; Binding Sites; Drug Discovery; Hydrophobic and Hydrophilic Interactions; Hypertension; Models, Biological; Molecular Dynamics Simulation; Renin; Thermodynamics

This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-κB and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice.

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Gene Expression; Hypertension; Kidney Tubules, Proximal; Mice; Mice, Transgenic; NF-E2-Related Factor 2; NF-kappa B; Pyrazines; Reverse Transcriptase Inhibitors; Signal Transduction; Thiones; Thiophenes

Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors.. Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n=3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction).. At baseline, transgenic rats had +18mmHg higher bood pressure and -8% lower body weight compared to non-transgenic rats (P<0.05) without significant changes for the vehicle groups throughout the study (P>0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P<0.05) in transgenic and +25%, +5.3% and +6.7% (P>0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P>0.05).. Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.

Topics: Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Enzyme Inhibitors; Humans; Hypertension; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Transgenic

Activation of renal renin-angiotensin system (RAS) and reactive oxygen species (ROS) are the main pathophysiological mechanisms associated with kidney injury both in diabetes and hypertension. However, the contribution to medullary damage when the two pathologies coexist has seldom been explored.. Diabetes was induced with streptozotocin in twelve week-old male Wistar and spontaneously hypertensive rats (SHR) rats; controls received vehicle. Three weeks later, systolic blood pressure (SBP), plasma and urinary angiotensinogen (AGT), renal oxidative stress and metabolic status were evaluated.. SBP was higher in SHR-controls than in Wistar-controls (200±6 and 127±3mmHg, respectively) and decreased in SHR-diabetics but not in Wistar-diabetics (143±8 and 122±6mmHg, respectively). Renal medullary hydrogen peroxide (H2O2) production was similarly increased in diabetics (Wistar: 0.32±0.04 and 1.11±0.10nmol/mg protein, respectively; SHR: 0.40±0.05 and 0.90±0.14nmol/mg protein, respectively) and positively correlated with glycemia (Wistar: r=0.7166, SHR: r=0.7899, p<0.05) and urinary AGT excretion (Wistar: r=0.8333; SHR: r=0.8326, p<0.05). Cortical H2O2 production was higher in SHR-controls than in Wistar-controls (1.10±0.09 and 0.26±0.04nmol/mg protein, respectively) and diabetes induction decreased it in SHR (0.70±0.09nmol/mg protein). Diabetes increased urinary AGT excretion by more than 7-fold and decreased plasma AGT concentration by more than 1.5-fold in both strains.. Our results show that STZ-induced diabetes increases medullary H2O2 production and urinary AGT excretion with similar magnitude in normotensive and hypertensive animals. Reducing blood pressure attenuates hypertension-associated cortical damage but does not prevent medullary dysfunction.

Topics: Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Hydrogen Peroxide; Hypertension; Kidney Cortex; Kidney Medulla; Male; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Wistar; Renin-Angiotensin System; Streptozocin

The aim of this study was to evaluate the association between blood pressure (BP) and urinary angiotensinogen excretion (uAGT) and renal sodium excretion (uNa) in children with type 1 diabetes mellitus (DM1).. The study group consisted of 52 children with DM1 (28 males and 24 females) with albumin/creatinine ratio (ACR) below 30 mg/g and glomerular filtration rate (eGFR) above 90 ml/min/1.73 m(2). BP was assessed by 24-h ambulatory blood pressure monitoring (ABPM).. The patients showed significantly increased uAGT values with respect to controls (median 0.00 and range 1.76 vs. 0.00 and 0.00 ng/mg, respectively). The significant increase of uAGT was observed even in prehypertensive patients. uAGT concentrations showed positive correlation with systolic and diastolic 24-h BP and with mean arterial pressure (MAP) (r = 0.594). uNa values were negatively correlated with BP parameters, uAGT, ACR and eGFR.. An increase in uAGT precedes hypertension (HTN) in normoalbuminuric children with DM1 and may be considered as a new marker of HTN. Decreased sodium excretion seems to be involved in the development of HTN and early renal injury. Both uAGT and uNa are associated with BP in normoalbuminuric diabetic children.

Topics: Adolescent; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Child; Diabetes Mellitus, Type 1; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Sodium

This study investigated the correlation between elevated serum uric acid (SUA) and angiotensinogen in obesity patients with hypertension. A total of 162 obese and 162 nonobese men with hypertension were recruited in this study. Plasma angiotensinogen levels were measured by enzyme-linked immunosorbent assay. Fasting insulin (FINS) was evaluated by radioimmunoassay. Compared with nonobese patients, obese patients exhibited higher levels of angiotensinogen, FINS, and homeostasis model assessment index-insulin resistance (HOMA-IR) (P<.001 for all). Moreover, these indexes significantly increased in obese patients in the highest tertile of SUA when compared with those in the lowest tertile of SUA (P<.001, P=.002, P=.007, respectively). In the obese group, SUA levels were significantly related to angiotensinogen, FINS, and HOMA-IR, respectively. Furthermore, it was demonstrated that obesity × uric acid was an independent contributor to angiotensinogen (β=0.257, P<.001). In conclusion, elevated SUA is strongly related to angiotensinogen in an obesity-dependent manner in hypertension.

Topics: Adipose Tissue; Adult; Angiotensinogen; Body Mass Index; Case-Control Studies; China; Homeostasis; Humans; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Uric Acid; Waist Circumference

Topics: Angiotensinogen; Humans; Hypertension; Male; Obesity; Uric Acid

Hypertension is a major global public health problem that affects both pediatric and adult populations. ACE I/D, AGT M235T, and ADD Gly460Trp polymorphisms are thought to be associated with primary hypertension. In the present study, we examined the frequency of these polymorphisms in a pediatric population with secondary hypertension.. Included in the study were 58 hypertensive and 58 normotensive pediatric patients. ACE I/D and AGT M235T polymorphisms are determined by conventional PCR; ADD Gly460Trp polymorphism was investigated using PCR amplification of genomic DNA.. There were significant differences between the control group and pediatric hypertensive group in terms of ACE I/D (P<0.05) and AGT M235T (P<0.05) polymorphisms, but there were no differences in ADD Gly460Trp (P>0.05) polymorphism.. We suggest that RAS gene polymorphisms (ACE-I/D, AGT M235T) are significantly associated with susceptibility to diseases that lead to secondary hypertension.

Topics: Alleles; Angiotensinogen; Calmodulin-Binding Proteins; Case-Control Studies; Child; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic

The roots of adult hypertension go back to childhood. This study aimed to examine the independent effects of physical, behavioural and genetic factors identified in childhood and mid-adulthood for prediction of adult hypertension.. The study subjects were participants of the Kaunas Cardiovascular Risk Cohort study started in 1977 (n = 1082, age 12-13 years). In 2012, a total of 507 individuals (63.9% of eligible sample) participated in the 35-year follow-up survey. Health examination involved measurements of blood pressure (BP), anthropometric parameters, and interview about health behaviours. Subjects were genotyped for AGT (M235T), ACE (I/D, rs4340), ADM (rs7129220), and CACNB2 (rs12258967) genes polymorphisms. A genetic risk score was calculated as the sum of the number of risk alleles at each of four single nucleotide polymorphisms.. AGT TT genotype male carriers had the highest mean values of systolic BP in childhood. In females, ADM genotype AA was associated with the highest values of systolic and diastolic BP, while CACNB2 genotype CC carriers had the highest values of diastolic BP in childhood. Systolic and diastolic BP in childhood, gain in BMI from childhood to adulthood, and risky alcohol consumption predicted hypertension in middle-aged men. In women, genetic risk score together with diastolic BP in childhood and gain in BMI were significant predictors of adult hypertension. The comparison of four nested logistic regression models showed that the prediction of hypertension improved significantly after the addition of BMI gain. Genetic risk score had a relatively weak effect on the improvement of the model performance in women.. BP in childhood and the gain in BMI from childhood to adulthood were significant predictors of adult hypertension in both genders. Genetic risk score in women and risky alcohol consumption in men were independently related with the risk of adult hypertension.

Topics: Adolescent; Adrenomedullin; Alcohol Drinking; Angiotensinogen; Body Mass Index; Calcium Channels, L-Type; Child; Female; Follow-Up Studies; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Lithuania; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Prevalence; Risk Factors

It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with ≥200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with ≥200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation.

Topics: Adult; Aged; Angiotensinogen; Chemokine CCL2; Creatine; Demography; Female; Follow-Up Studies; Humans; Hypertension; Male; Malondialdehyde; Middle Aged; Reactive Oxygen Species; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sodium, Dietary; Urine Specimen Collection

Patients with type 2 diabetes (T2D) are at high risk of developing hypertension and related cardiovascular disease. The renin-angiotensin system (RAS) plays a central role in regulation of blood pressure (BP). Accordingly, each component of this system represents a potential candidate in the etiology of hypertension. This study investigated the impact of polymorphisms within the RAS on ambulatory and central BP in T2D subjects. A cohort of 761 subjects (55-65 years) with T2D was studied. Ambulatory and central BP were measured, and ACE I/D genotype, angiotensinogen M235T, renin rs6693954 and ATR1-A1166C polymorphisms were analyzed. Women carrying the AA-genotype had lower 24-hour and day-time systolic and diastolic BP (p<0.05), and lower night-time and central diastolic BP (p<0.05), compared to T allele carriers. In men, the AA-genotype was instead associated with higher central diastolic BP (p=0.018) and higher augmentation index (p=0.016). Further, the associations between the renin rs6693954 SNP and diastolic BP were strongly gender dependent (p≤0.001). In T2D patients, there is a gender-dependent association of the renin rs6693954 SNP with central and ambulatory BP. Women carrying the renin rs6693954 AA-genotype may be protected against the higher BP seen in men with the same genotype.

Topics: Aged; Angiotensinogen; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System

Topics: Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Female; Humans; Hypertension; Male

Topics: Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Female; Humans; Hypertension; Male

The angiotensinogen M235T and aldosterone synthase C-344T gene polymorphisms have been associated with cardiac and structure function. However, these associations in untreated hypertension remain unknown. We examined whether these variants determined both echocardiography indices and the potential associated underlying mechanisms, including cystatin-C and vascular inflammation.. The study population consisted of 319 untreated patients and 191 healthy individuals. Polymorphisms were determined by polymerase chain reaction technique. Left cardiac indices of geometry and function were assessed by echocardiography. Cystatin-C, intracellular cell adhesion molecule 1, and vascular cell adhesion molecule 1 levels were measured by enzyme-linked immunosorbent assay, whereas high sensitivity C-reactive protein levels were measured by immunonephelometry.. There was no significant interaction between the angiotensinogen genotypes on left ventricular mass index (LVMI) and diastolic function indices in all study groups. Regarding C-344T polymorphism, TT homozygous hypertensive subjects exhibited higher values of LVMI compared with C allele carriers (P = 0.02) and higher prevalence of concentric hypertrophy (P < 0.001). However, this polymorphism was not associated with variations in left atrial volume and diastolic dysfunction. Cystatin-C levels were correlated with LVMI values (r = 0.22; P = 0.002) and mean E/A ratio (r = -0.24; P < 0.001). Interestingly, a linear increase of LVMI with cyctatin-C quartiles has been revealed (F = 5.01; P < 0.001). Moreover, post hoc tests showed that increased levels of cystatin-C (above 75th percentile) were significantly different between both the first (P = 0.009) and the second quartile (P = 0.02).. We have shown that C-344T potentially predicts higher values of LVMI and concentric hypertrophy in untreated hypertension, independently of renal function and subclinical inflammation. Increased levels of cystatin-C were correlated with higher LVMI values.

Topics: Adult; Aged; Alleles; Angiotensinogen; Biomarkers; C-Reactive Protein; Case-Control Studies; Cystatin C; Cytochrome P-450 CYP11B2; Echocardiography; Female; Genetic Predisposition to Disease; Humans; Hypertension; Hypertrophy, Left Ventricular; Intercellular Adhesion Molecule-1; Male; Middle Aged; Prevalence; Vascular Cell Adhesion Molecule-1

We studied the expression of genes encoding angiotensinogen (Agt), renin (Ren), angiotensin-converting enzyme (ACE), and type 1 angiotensin receptor (AT1A) in the hypothalamus and medulla oblongata of hypertensive ISIAH rats and normotensive WAG rats. The amount of Agt mRNA in the hypothalamus of young ISIAH rats was increased by 30% compared to WAG controls. In the medulla oblongata of young ISIAH rats, the levels of mRNA of Agt and AT1A receptor were enhanced by 60% and 24%, respectively, compared to WAG rats. In adult animals, the expression of the studied genes did not differ from the control. It is concluded that changes in gene expression of the renin-angiotensin system in brain structures of ISIAH rats may contribute to the development of hypertension.

Topics: Angiotensinogen; Animals; Blood Pressure; Brain; Hypertension; Hypothalamus; Male; Medulla Oblongata; Peptidyl-Dipeptidase A; Rats; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; RNA, Messenger; Stress, Physiological

Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals.. Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System.. Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ² = 7.02; p = 0.0081) and another GGCGGAGT (χ² = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2 = 5.66; p = 0.017) and ATTGAGAC (χ² = 5.93; p = 0.015), obesity with GGCGGAGT (χ² = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ² = 6.68; p = 0.010) and GGTGGGAT (χ² = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD.. These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.

Topics: Angiotensinogen; Arabs; Case-Control Studies; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; DNA Mutational Analysis; Female; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Logistic Models; Male; Middle Aged; Obesity; Odds Ratio; Oligonucleotide Array Sequence Analysis; Phenotype; Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; Risk Assessment; Risk Factors; Saudi Arabia

Experimental and epidemiological studies have demonstrated that urinary angiotensinogen (AGT) is a novel biomarker for the intrarenal activity of the renin-angiotensin system in hypertension (HT). Several large-scale epidemiological studies have shown that an elevated serum uric acid (SUA) level is associated with HT. The aim of our study was to assess urinary AGT excretion and its correlation with SUA level, the lipid profile, and the body mass index (BMI) Z-score in hypertensive adolescents.. Participants were divided into two groups: (1) the group with confirmed HT consisting of 55 subjects with primary HT and (2) the reference (R) group consisting of 33 subjects with white-coat HT. A commercial enzyme-linked immunosorbent assay (ELISA) kit was used to determine urinary AGT concentration.. The urinary AGT/creatinine (cr.) ratio in subjects in the HT group was significantly higher than that in the reference group (p < 0.01) and showed a strong positive correlation with SUA (r = 0.47, p < 0.01). The relationship between the AGT/cr. ratio and SUA levels after controlling for age, gender and BMI Z-score continued to show a significant association.. The most obvious finding to emerge from this study is that in adolescents with primary HT, the increased urinary excretion of AGT correlated with hyperuricemia, although large, multicenter studies are needed to confirm this observation.

Topics: Adolescent; Angiotensin II; Angiotensinogen; Biomarkers; Body Mass Index; Chi-Square Distribution; Child; Creatinine; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Hyperuricemia; Kidney; Linear Models; Lipids; Male; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; Up-Regulation; Uric Acid

We investigated the relationship among oxidative stress, hypertension, renal injury, and angiotensin-converting enzyme-2 (ACE2) expression in type 1 diabetic Akita mice. Blood glucose, blood pressure, and albuminuria were monitored for up to 5 mo in adult male Akita and Akita catalase (Cat) transgenic (Tg) mice specifically overexpressing Cat, a key antioxidant enzyme in their renal proximal tubular cells (RPTCs). Same-age non-Akita littermates and Cat-Tg mice served as controls. In separate studies, adult male Akita mice (14 wk) were treated with ANG 1-7 (500 μg·kg⁻¹·day⁻¹ sc) ± A-779, an antagonist of the Mas receptor (10 mg·kg⁻¹·day⁻¹ sc), and euthanized at the age of 18 wk. The left kidneys were processed for histology and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess protein and gene expression. Urinary angiotensinogen (AGT), angiotensin II (ANG II), and ANG 1-7 were quantified by specific ELISAs. Overexpression of Cat attenuated renal oxidative stress; prevented hypertension; normalized RPTC ACE2 expression and urinary ANG 1-7 levels (both were low in Akita mice); ameliorated glomerular filtration rate, albuminuria, kidney hypertrophy, tubulointerstitial fibrosis, and tubular apoptosis; and suppressed profibrotic and proapoptotic gene expression in RPTCs of Akita Cat-Tg mice compared with Akita mice. Furthermore, daily administration of ANG 1-7 normalized systemic hypertension in Akita mice, which was reversed by A-779. These data demonstrate that Cat overexpression prevents hypertension and progression of nephropathy and highlight the importance of intrarenal oxidative stress and ACE2 expression contributing to hypertension and renal injury in diabetes.

Topics: Albuminuria; Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Apoptosis; Catalase; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fibrosis; Hypertension; Kidney; Kidney Tubules; Kidney Tubules, Proximal; Male; Mice; Mice, Transgenic; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A

Exaggerated blood pressure response (EBPR) during the exercise treadmill test (ETT) has been considered to be a risk factor for hypertension. The relationship of polymorphisms of the renin-angiotensin system gene with hypertension has not been established. Our objective was to evaluate whether EBPR during exercise is a clinical marker for hypertension. The study concerned a historical cohort of normotensive individuals. The exposed individuals were those who presented EBPR. At the end of the observation period (41.7 months = 3.5 years), the development of hypertension was analyzed within the two groups. Genetic polymorphisms and blood pressure behavior were assessed as independent variables, together with the classical risk factors for hypertension. The I/D gene polymorphism of the angiotensin-converting enzyme and M235T of angiotensinogen were ruled out as risk factors for hypertension. EBPR during ETT is not an independent influence on the chances of developing hypertension. No differences were observed between the hypertensive and normotensive individuals regarding gender (P = 0.655), skin color (P = 0.636), family history of hypertension (P = 0.225), diabetes mellitus (P = 0.285), or hypertriglyceridemia (P = 0.734). The risk of developing hypertension increased with increasing body mass index (BMI) and advancing age. The risk factors, which independently influenced the development of hypertension, were age and BMI. EBPR did not constitute an independent risk factor for hypertension and is probably a preclinical phase in the spectrum of normotension and hypertension.

Topics: Adolescent; Adult; Age Factors; Aged; Angiotensinogen; Blood Pressure; Body Mass Index; Cohort Studies; Exercise Test; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Retrospective Studies; Risk Factors; Young Adult

We investigated whether heterogeneous nuclear ribonucleoproteins F and K (hnRNP F, hnRNP K) mediate insulin inhibition of renal Agt expression and prevention of hypertension and kidney injury in an Akita mouse model of type 1 diabetes.. Adult male Akita mice (12 weeks old) were treated with insulin implants and killed at week 16. Untreated non-Akita littermates served as controls. The effects of insulin on blood glucose, systolic BP (SBP), renal proximal tubular cell (RPTC) gene expression and interstitial fibrosis were studied. We also examined immortalised rat RPTCs stably transfected with control plasmid or with plasmid containing rat Agt promoter in vitro.. Insulin treatment normalised blood glucose levels and SBP, inhibited renal AGT expression but enhanced hnRNP F, hnRNP K and angiotensin-converting enzyme-2 expression, attenuated renal hypertrophy and glomerular hyperfiltration and decreased urinary albumin/creatinine ratio, as well as AGT and angiotensin II levels, in Akita mice. In vitro, insulin inhibited Agt but stimulated Hnrnpf and Hnrnpk expression in high-glucose media via p44/42 mitogen-activated protein kinase signalling in RPTCs. Transfection with Hnrnpf or Hnrnpk small interfering RNAs prevented insulin inhibition of Agt expression in RPTCs.. These data indicate that insulin prevents hypertension and attenuates kidney injury, at least in part, through suppressing renal Agt transcription via upregulation of hnRNP F and hnRNP K expression in diabetic Akita mice. HnRNP F and hnRNP K may be potential targets in the treatment of hypertension and kidney injury in diabetes.

Topics: Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Hypertension; Insulin; Kidney; Male; Mice

Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol·kg(-1)·min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Chymases; Disease Models, Animal; Hypertension; Infusions, Intravenous; Lisinopril; Male; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Gene silencing by RNA interference (RNAi) is a promising approach for gene therapy. However, up to today, it is still a major challenge to find safe and efficient non-viral vectors. Previously, we reported PEI-Bu, a small molecular weight PEI derivative, as an efficient non-viral carrier. However, like many PEI-based polymers, PEI-Bu was too toxic. In order to reduce cytotoxicity while maintain or even enhance transfecion efficiency, we modified PEI-Bu with poly(ethylene glycol) (PEG) to obtain PEG-Bu, and used it to delivery a theraputic short hairpin RNA (shRNA) targeting angiotensinogen (AGT) to normal rat liver cells (BRL-3A), which was a key target for the treatment of hypertension. The structure of PEG-Bu was confirmed by proton nuclear magnetic resonance ((1)H-NMR). Gel permeation chromatography (GPC) showed that the weight average molecular weight (Mw) of PEG-Bu was 5880 Da, with a polydispersity of 1.58. PEG-Bu could condense gene cargo into spherical and uniform nanoparticles with particle size (65-88 nm) and zeta potential (7.3-9.6 mV). Interestingly and importantly, PEG-Bu displayed lower cytotoxicity and enhanced tranfection efficiency than PEI-Bu after PEGylation in both normal cells BRL-3A and tumor cells HeLa. Moreover, PEG-Bu could efficiently delivery AGT shRNA to knockdown the AGT expression. To sum up, PEG-Bu would be a promising non-viral vector for delivering AGT shRNA to BRL-3A cells for hypertension therapy.

Topics: Angiotensinogen; Animals; Cell Line; Gene Silencing; Gene Transfer Techniques; Humans; Hypertension; Imines; Molecular Weight; Plasmids; Polyethylenes; Rats; RNA Interference; RNA, Small Interfering; Transfection

Inappropriate activation of the intrarenal renin-angiotensin system induces generation of reactive oxygen species and tubulointerstitial inflammation, which contribute to salt-sensitive hypertension (SSHT). Liver-type fatty acid-binding protein is expressed in proximal tubules in humans, but not in rodents, and may play an endogenous antioxidative role. The objective of the present study was to examine the antioxidative effect of liver-type fatty acid-binding protein on post-angiotensin II SSHT model in transgenic mice with selective overexpression of human liver-type fatty acid-binding protein in the proximal tubules. The transgenic mice showed marked protection against angiotensin II-induced SSHT. Overexpression of tubular liver-type fatty acid-binding protein prevented intrarenal T-cell infiltration and also reduced reactive oxygen species generation, intrarenal renin-angiotensin system activation, and monocyte chemotactic protein-1 expression. We also performed an in vitro study using the murine proximal tubular cell lines with or without recombinant liver-type fatty acid-binding protein and murine proximal tubular cell lines transfected with human liver-type fatty acid-binding protein, and found that gene transfection of liver-type fatty acid-binding protein and, in part, recombinant liver-type fatty acid-binding protein administration had significantly attenuated angiotensin II-induced reactive oxygen species generation and the expression of angiotensinogen and monocyte chemotactic protein-1 in murine proximal tubular cell lines. These findings indicated that liver-type fatty acid-binding protein in the proximal tubules may protect against angiotensin II-induced SSHT by attenuating activation of the intrarenal renin-angiotensin system and reducing oxidative stress and tubulointerstitial inflammation. Present data suggest that liver-type fatty acid-binding protein in the proximal tubules may be a novel therapeutic target for SSHT.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Fatty Acid-Binding Proteins; Hypertension; Inflammation; Kidney; Kidney Tubules, Proximal; Mice; Mice, Transgenic; Oxidative Stress; Reactive Oxygen Species; Renin-Angiotensin System

Early onset of hypertension and its consequences account for the great majority of deaths in patients with autosomal dominant polycystic kidney disease (ADPKD). Renin-angiotensin system (RAS) components have been shown in ADPKD kidneys independent of systemic RAS. Thus, we examined the urinary angiotensinogen (UAGT) levels as a biomarker of intrarenal RAS status in ADPKD patients with/without hypertension and healthy subjects.. Eighty-four ADPKD patients (43 with hypertension and 41 without hypertension) and 40 healthy controls were studied cross-sectionally. Patients with glomerular filtration rate <60 ml/min were excluded from the study. Hypertension was diagnosed with ambulatory blood pressure monitoring. Urinary and plasma concentration of angiotensinogen, spot urine microprotein and creatinine (UCre) levels were recorded for each participant.. UAGT/UCre levels were higher in hypertensive ADPKD patients (23.7 ± 8.4) compared with normotensive ADPKD patients (16.6 ± 5.2) and healthy controls (6.9 ± 3.3; p < 0.001). In univariate analysis, UAGT correlated with systolic blood pressure, diastolic blood pressure (DBP) and proteinuria. The independence of these correlations was analyzed in a regression model, and UAGT was shown to be significantly predicted by proteinuria and DBP.. Intrarenal RAS activation which is monitored by UAGT levels clinically may be a harbinger of hypertension and kidney disease in ADPKD patients.

Topics: Adult; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Case-Control Studies; Cohort Studies; Creatinine; Cross-Sectional Studies; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Proteinuria; Regression Analysis; Renin-Angiotensin System

In the current study, we measured urinary angiotensinogen (AGT) through enzyme-linked immunoadsordent assay (ELISA) and analyzed its correlation with intrarenal renin-angiotensin system (RAS) activity in 128 chronic kidney disease (CKD) patients. Urinary and plasma renin activity, AGT, angiotensin II (Ang II) and aldosterone levels were also measured by radioimmunoassay (RIA) or ELISA in these participants. Further, the expression level of intrarenal renin, AGT, Ang II and Ang II receptors were examined by immunohistochemistry staining (IHCS) in 72 CKD patients. Their correlations with urinary AGT were also analyzed. We found that the urinary AGT level was positively correlated with hypertension (ρ = 0.28, P < 0.01), urinary protein (r = 0.38, P < 0.01), urinary Ang II (r = 0.29, P < 0.05), urinary type IV collagen (Col IV) (r = 0.56, P < 0.01), and was negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.28, P < 0.01), urinary sodium (r = -0.22, P < 0.05) and serum AGT (r = -0.27, P < 0.01). Multiple regression analysis indicated low serum AGT (P < 0.01), high urinary protein (P < 0.01), high urinary Ang II (P < 0.05) and high urinary Col IV (P < 0.01) were correlated significantly with high urinary AGT. Urinary AGT level was positively correlated with intrarenal expression level of AGT (ρ = 0.46, P < 0.01), Ang II (ρ = 0.56, P < 0.01) and Ang II type 1 receptor (ρ = 0.32, P < 0.01), as detected by IHCS. Together, these data suggest that urinary AGT might be a potential biomarker of intrarenal RAS and Ang II activities in CKD patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin II; Angiotensinogen; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Regression Analysis; Renal Insufficiency, Chronic; Renin-Angiotensin System; Young Adult

This study examined renin-angiotensin-aldosterone (RAAS) system gene variants for associations with cardiovascular risk factors and outcomes in coronary heart disease. Coronary disease patients (n=1186) were genotyped for 21 single-nucleotide polymorphisms (SNPs) within angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin-II type-1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Associations with all-cause mortality and cardiovascular readmissions were assessed over a median of 3.0 years. The AGT M235T 'T' allele was associated with a younger age of clinical coronary disease onset (P=0.006), and the AGT rs2478545 minor allele was associated with lower circulating natriuretic peptides (P=0.0001-P=0.001) and E/E(1) (P=0.018). Minor alleles of AGT SNPs rs1926723 and rs11122576 were associated with more frequent history of renal disease (P0.04) and type-2 diabetes (P0.02), higher body mass index (P0.02) and greater mortality (P0.007). AGT rs11568054 minor allele carriers had more frequent history of renal disease (P=0.04) and higher plasma creatinine (P=0.033). AGT rs6687360 minor allele carriers exhibited worse survival (P=0.02). ACE rs4267385 was associated with older clinical coronary disease onset (P=0.008) and hypertension (P=0.013) onset, increased plasma creatinine (P=0.01), yet greater mortality (P=0.044). Less history of hypertension was observed with the AGTR1 rs12685977 minor allele (P=0.039). Genetic variation within the RAAS was associated with cardiovascular risk factors and accordingly poorer survival.

Topics: Age of Onset; Aged; Angiotensinogen; Comorbidity; Coronary Artery Disease; Cytochrome P-450 CYP11B2; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; New Zealand; Odds Ratio; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Single Nucleotide; Prognosis; Proportional Hazards Models; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Assessment; Risk Factors; Time Factors

Renin-angiotensin and kallikrein-kinin systems are interconnected, regulating blood pressure homeostasis. We have demonstrated the interactions among polymorphisms of the angiotensinogen (AGT) and endothelial nitric oxide synthase (NOS3) genes and conventional risk factors affecting the hypertension occurrence. Individuals were recruited (n=192) and classified into hypertensive (HG; n=140) and normotensive (NG; n=52) groups. The genotypic distribution of the Met235Thr (AGT) and Glu298Asp (NOS3) polymorphisms demonstrated that both are independent risk factors of hypertension (p=0.02 and p=0.008, respectively). The concomitant presence of these polymorphisms in the HG group was significantly different (p=0.001) from the NG. Both gene polymorphisms presented an additive effect for the unfavourable alleles T and A, respectively, and 95% of the double mutant homozygotes were classified into the HG. Specific interactions among certain conventional factors and the presence of at least one unfavourable allele presented significant odds towards hypertension. Blood pressure homeostasis was affected by genetic polymorphisms conditioned by the T and A alleles of the AGT and NOS3 genes, respectively, which acted independently. However, their interaction with smoking, sedentariness, age and total cholesterol may have increased the predisposition to hypertension, which may explain most of the hypertension cases.

Topics: Alleles; Angiotensinogen; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Nitric Oxide Synthase Type III; Odds Ratio; Polymorphism, Single Nucleotide; Regression Analysis; Risk Factors

A total of 180 hypertensive and 188 normotensive subjects were studied for demographic features and for variations in exon 4 including exon-intron boundary of AGT gene using single-strand conformation polymorphism analysis. Sequencing of the samples showing mobility shift revealed a single-nucleotide polymorphism variant g.15241A>G in intron 3 of the gene. The polymorphism was consistent with Hardy-Weinberg equilibrium in both the cases and the controls. Although the genotype distribution and allele frequencies did not differ significantly in general, high risk was observed for males with G allele (OR = 2.08; 95% CI = 1.02-4.21; P = .04). Similar results were obtained when the genotypes were tested in dominant model wherein G allele carriers were found to be at twofold risk for developing essential hypertension (OR = 2.09; 95% CI = 0.99-4.41; P = 0.05). This report is the first one in the literature showing association of g.15241A>G polymorphism with a clinical condition.

Topics: Angiotensinogen; Blood Pressure; Female; Genetic Predisposition to Disease; Humans; Hypertension; Introns; Male; Middle Aged; Polymorphism, Single-Stranded Conformational; Risk Factors; Sex Distribution

Melusin is an integrin β1-interacting protein proposed to act as a biomechanical sensor in the heart. We characterized mechanisms and signalling pathways regulating cardiac melusin expression.. Infusion of arginine(8) -vasopressin (AVP) in Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHR) and double transgenic rats (dTGR) harbouring both human angiotensinogen and renin genes as well as infusion of angiotensin II (Ang II) in SD rats were used. The effect of direct left ventricular (LV) wall stretch was analysed by using isolated perfused rat heart preparation. For the cell culture studies, mouse atrial HL-1 cell line and neonatal rat ventricular myocytes (NRVMs) were used.. Left atrial melusin mRNA levels increased already after 30 min of AVP infusion. Ang II caused significant upregulation of left atrial melusin mRNA (2.1-fold at 6 h, P < 0.05) and protein (1.9-fold at 72 h, P < 0.05) levels. In contrast, LV melusin mRNA levels remained unchanged in response to both infusions, as well as to aortic banding-induced pressure overload. Direct LV wall stress or late-stage hypertensive heart disease did not modify LV melusin gene expression either. Interestingly, in atrial HL-1 cells, cyclic stretching increased melusin mRNA levels. Stretching and treatments with hypertrophic agonists increased melusin mRNA and protein levels in NRVMs, endothelin-1 being the most potent. PD98059, an extracellular signal-regulated protein kinase 1/2 inhibitor, markedly attenuated the endothelin-1-induced upregulation of melusin gene expression in NRVMs.. Multiple hypertrophic stimuli regulate melusin expression predominately in the atria, which may represent a necessary initial step in early adaptive remodelling processes.

Topics: Angiotensinogen; Animals; Animals, Newborn; Arginine Vasopressin; Cell Line; Cytoskeletal Proteins; Disease Models, Animal; Gene Expression Regulation; Heart Atria; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Mice; Muscle Proteins; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Rats, Transgenic; Renin; RNA, Messenger; Signal Transduction; Time Factors

Human essential hypertension is partly caused by genetic factors. Angiotensinogen (AGT), G-protein β3-subunit (GNB3) and cytochrome P450 3A5 (CYP3A5) are candidate hypertension susceptibility genes and risk alleles at these loci have been thought to arise owing to human adaptation to climatic changes following the migration out-of-Africa. This study aimed to reveal the frequencies of hypertension-susceptibility genotypes in Pacific Island populations and associations of these single-nucleotide polymorphisms (SNPs) to hypertension. Genotyping was conducted for 804 individuals from Melanesian, Micronesian and Polynesian populations at SNPs in the genes encoding AGT (rs699, rs5049 and rs5051), GNB3 (rs5443) and CYP3A5*1/*3 (rs776746). Associations between these SNPs and hypertension were tested for 383 Melanesian Solomon Islanders. We found that the A/A genotype at rs5049 was a risk factor for hypertension (P=0.025) in the Melanesian Solomon Islanders; three SNPs for AGT were in linkage disequilibrium. The ancestral alleles of rs699, rs5051 and rs776746, and the derived allele of rs5443 were as frequent in the populations surveyed here as in other equatorial populations. Although other polymorphisms associated with hypertension and additional populations remain to be studied, these findings suggest that the Pacific Islanders' susceptibility to hypertension arose because of human migration and adaptation.

Topics: Adolescent; Adult; Aged; Alleles; Angiotensinogen; Cytochrome P-450 CYP3A; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetics, Population; Heterotrimeric GTP-Binding Proteins; Human Migration; Humans; Hypertension; Linkage Disequilibrium; Male; Melanesia; Middle Aged; Pacific Islands; Polymorphism, Single Nucleotide; Prevalence; Risk Factors; Young Adult

Several studies have reported the association of genes related to vascular tone, hypertension, oxidative stress and preeclampsia. We investigated the possible association among three polymorphisms in eNOS (as well their haplotypes): one of MTHFR, one of GSTP1 and one of AGT, with severe preeclampsia in Mexican-Mestizo women.. Two hundred thirty women with severe preeclampsia and 350 control subjects were genotyped; for rs2070744 and rs1799983 of eNOS, rs1801133 of MTHFR, rs1695 of GSTP1 and rs699 of AGT we used real-time PCR allelic discrimination and for VNTR of eNOS, PCR. Allele frequency differences were assessed by χ(2). Logistic regression was used to test for associations and for haplotype frequencies using Haploview 4.2.. Genotypic and allelic distribution of the polymorphisms was similar between cases and controls; likewise, haplotype frequencies of the three polymorphisms of eNOS did not differ significantly.. To our knowledge, this is the first time that these polymorphisms have been analyzed together and exclusively in women with severe preeclampsia. However, we did not find an association between polymorphisms of eNOS, MTHFR, GSTP1 and AGT with severe preeclampsia in our population. Additionally, we observed differences in the distribution of the alleles and genotypes of these polymorphisms in our population in comparison to those described in other ethnic groups.

Topics: Adult; Angiotensinogen; Female; Glutathione S-Transferase pi; Haplotypes; Humans; Hypertension; Methylenetetrahydrofolate Reductase (NADPH2); Mexico; Nitric Oxide Synthase Type III; Oxidative Stress; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy

Apelin, a novel multifunctional peptide implicated in the regulation of the cardiovascular system, including blood pressure and cardiac function control, has been postulated to be involved in the pathophysiology of hypertension and hypertensive heart disease. The aim of this study was to investigate, for the first time, whether the effects of apelin's chronic application might be involved in deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). In this study, 8-10-week-old male Wistar rats were divided into four groups: control, control + apelin, DOCA-salt rats, DOCA-salt rats + apelin. Deoxycorticosterone Acetate (25 mg/kg of body weight) was injected subcutaneously, twice a week for 4 weeks. These rats received NaCl 1% instead of tap water for drinking during the experimental period. Later, rats were randomly treated with pyroglutamylated apelin-13 (200 μg. kg(-1). day(-1) intraperitonealy) for 17 days. The concentrations of apelin, endothelin-1, angiotensin-converting enzyme, angiotensinogen, and angiotensin II were analyzed in the plasma. The mRNA level of apelin and apelin receptor were determined in the heart and aorta tissue by real-time polymerase chain reaction, respectively. It was found that apelin reduces blood pressure in DOCA-salt rats. Apelin can be used as a therapeutic agent in the treatment of hypertension in the future.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Aorta; Apelin; Apelin Receptors; Blood Pressure; Desoxycorticosterone Acetate; Endothelin-1; Hypertension; Intercellular Signaling Peptides and Proteins; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin-Angiotensin System; RNA, Messenger

Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (angiotensin-converting enzyme (ACE) insertion/deletion (I/D); angiotensinogen (AGT) -6G-A, M235T, -20A-C) in the renin-angiotensin system on left ventricular mass (LVM) among hypertensive participants in the Hypertension Genetic Epidemiology Network study. Included were 2156 participants aged 20-87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: adjusted mean LVM (gm(-2.7)) increased with 'G' allele copy number ('AA':41.2, 'AG':42.3, 'GG':44.0; P=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction P=0.03): among ACE 'DD' participants, AGT -20A-C 'C' allele carriers had lower mean LVM than 'AA' homozygotes ('DD/CC':39.2, 'DD/AC':39.9, 'DD/AA':43.9), with no similar significant effect among ACE 'I' allele carriers ('ID/CC':47.2, 'ID/AC':43.4, 'ID/AA':42.6; 'II/CC': NA, 'II/AC':41.3, 'II/AA':43.1). These findings indicate that renin-angiotensin system variants in at least two genes may interact to modulate LVM.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Black or African American; Chi-Square Distribution; Epistasis, Genetic; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Homozygote; Humans; Hypertension; Hypertrophy, Left Ventricular; Linear Models; Male; Middle Aged; Peptidyl-Dipeptidase A; Phenotype; Risk Assessment; Risk Factors; United States; White People; Young Adult

Even after excellent repair of aortic coarctation without restenosis there are limitations in exercise capacity at long-term follow-up. This study was performed to assess the contribution of inherited genomic polymorphisms to exercise capacity in patients without restenosis.. 122 patients aged 17-72 years, 46 female, 76 male, seen 2-27 years after repair of aortic coarctation with a residual brachial-ankle-gradient ≤20 mmHg were investigated. Genomic polymorphism of angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT, c.704C > T), angiotensin II receptor type 1 (AGTR1, c.1166A > C), endothelin 1 (EDN1, EDN1/ex5-c.5665G > T), G protein (GNB3, c.825C > T), and two polymorphisms each of the ß1-adrenoreceptor (ADRB1, c.145G > A and c.1165C > G), ß2-adrenoreceptor (ADRB2, c.46A > G and c.79C > G), and endothelial NO synthase (NOS3, intron 4 I/D and NOS3, c.894G > T) were determined by PCR amplification and fragment length analysis. Exercise capacity was determined by an upright bicycle exercise test.. Only the c.46A > G polymorphism of the ADRB2 (p = 0.024) and the c.704T > C AGT polymorphism (p = 0.042) were positively correlated with peak workload. Patients with one or especially two polymorphic alleles showed a significant higher exercise performance compared with those patients homozygous for the wild type.. In contrast to a previous study in heart failure patients, after coarctation repair adults had a better exercise capacity with the G allele of the ß2-receptor c.46A > G polymorphism. Therefore, the exercise capacity of coarctation patients does not profit from an enhanced down regulation of their beta receptors.

Topics: Adolescent; Adult; Aged; Angiotensinogen; Aortic Coarctation; Down-Regulation; Exercise Test; Exercise Tolerance; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prospective Studies; Receptors, Adrenergic, beta-2; Young Adult

Essential hypertension (HTA) is the clinical expression of a disordered interaction between the genetic, physiological, and biochemical systems that under usual conditions maintain cardiovascular homeostasis. We studied the effects of the angiotensinogen M235T, angiotensin converting enzyme insertion/deletion (ACE I/D), and angiotensin II receptor 1 (AT1R) A1166C gene polymorphisms on the risk of HTA and to evaluate the relationship between these polymorphisms and obesity. We performed AGT, ACE and AGTR genotyping in 142 hypertensive patients and 191 control subjects using PCR-RFLP methods and PCR, respectively. The three polymorphisms were significantly associated with HTA. Individuals carrying the mutated TT of AGT, DD of ACE and CC of AT1R genotypes had an 1.67 (P = 0.032), 3.09 (P < 0.001) and 3.45 (P < 0.001)-fold increased risk of HTA. After adjustment for sex, smoking, diabetes, dyslipidemia, BMI, triglycerides and DD, TT and CC genotypes, BMI was independent risk factor of HTA (OR = 3.14; P < 0.001). An association of BMI with ACE gene polymorphism (P = 0.035), whereas no association with AGT and AT1R gene polymorphisms was obtained. The proportion of hypertensives is as high as 21.8 and 13.4% in the overweight and the obese DD group. The present study implies that the genotyping for the variants of RAS gene could in the future become an important part of the clinical process of risk identification for HTA.

Topics: Aged; Angiotensinogen; Body Mass Index; Case-Control Studies; Confidence Intervals; Demography; Female; Genetic Predisposition to Disease; Genetics, Population; Humans; Hypertension; Logistic Models; Male; Middle Aged; Obesity; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Tunisia

Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n = 5]; 2) HS diet [8% NaCl, n = 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n = 5]; 4) ANG II infusion in HS rats [ANG II+HS, n = 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG II+HS+ARB, n = 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 ± 10 vs. 221 ± 8 mmHg; P < 0.05), proteinuria (46 ± 7 vs. 127 ± 7 mg/day; P < 0.05), and uAGT (1,109 ± 70 vs.. 7,200 ± 614 ng/day; P < 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O(2)(-) levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Hypertension; Kidney; Male; NADPH Oxidases; Oxidative Stress; Peroxynitrous Acid; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Sodium Chloride, Dietary

Obesity-related hypertension may be caused by activation of the local adipose tissue renin-angiotensin system, resulting in exaggerated production of the vasoconstrictor angiotensin II. Additionally, secretion of adiponectin from adipose tissue, which prevents endothelial dysfunction, is altered in obesity. Consumption of conjugated linoleic acid (CLA) has been shown to modulate cytokine release from adipocytes and positively influence blood pressure in younger rats, but its physiological actions in older models with established hypertension and isomer-specific effects on adipocyte size remain to be determined. Therefore, we investigated the effects of CLA isomers on adipocyte size in relation to blood pressure and adipokine production by hypertrophic adipocytes in older fa/fa Zucker rats with established hypertension. fa/fa Zucker rats were fed with cis(c)9, trans(t)11-CLA or t10, c12-CLA isomers for 8 weeks and compared with lean and obese rats fed with the control diet. Blood pressure and adipocyte size were subsequently measured. Collagenase-isolated adipocytes were size-separated and angiotensinogen and adiponectin protein levels quantified by Western blotting. The t10, c12-CLA group had reduced blood pressure, fewer large adipocytes and increased serum adiponectin. Angiotensinogen was present at higher levels in the large adipocytes, whereas the converse was observed for adiponectin. The beneficial effects of the t10, c12-CLA isomer on blood pressure and adipocyte size in vivo may be due to its ability to reduce the number of large adipocytes, which alters the levels of vasoactive molecules secreted from adipose tissue.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Angiotensinogen; Animals; Anti-Obesity Agents; Antihypertensive Agents; Blood Pressure; Blotting, Western; Collagenases; Dietary Fats; Hypertension; Hypertrophy; Isomerism; Linoleic Acids, Conjugated; Male; Obesity; Rats; Rats, Zucker

Previous studies on the effects of angiotensinogen (AGT) gene polymorphisms and chronic exposure to occupational noise on the risk of hypertension have mainly been cross-sectional or prevalent case-control studies, where temporality constitutes problems. The present study was to assess longitudinally both independent and joint effects of AGT gene polymorphisms and chronic exposure to occupational noise on occurrence of hypertension.. The authors conducted a 20-year prospective cohort study of 1301 aviation workers in Taiwan. The study population included 912 workers without hypertension at baseline. The outcome of interest was the development of hypertension during the study period. The studied determinants were three AGT genotypes (TT, TM and MM) and four exposure categories according to the levels of noise representing high (>80 dBA), medium (80-65 dBA), low exposure (64-50 dBA) and the reference level (49-40 dBA).. In Poisson regression adjusting for confounders, AGT (TT vs MM adjusted incidence rate ratio (IRR) 1.77, 95% CI 1.24 to 2.51) and noise exposure (high and medium combined) during 3-15 years (adjusted IRR 2.35, 95% CI 1.42 to 3.88) were independent determinants of hypertension. Furthermore, the risk of hypertension increased with noise exposure (adjusted IRR 3.73, 95% CI 1.84 to 7.56) among TT homozygotes but not among those with at least one M allele (Rothman synergy index=1.05).. The results evidence further the independent effects of AGT gene polymorphisms and exposure to occupational noise. Our finding also suggests that workers carrying TT variant allele have higher risk of hypertension under chronic exposure to occupational noise.

Topics: Adult; Aircraft; Alleles; Angiotensinogen; Female; Gene-Environment Interaction; Genotype; Homozygote; Humans; Hypertension; Incidence; Industry; Longitudinal Studies; Male; Middle Aged; Noise, Occupational; Occupational Exposure; Poisson Distribution; Polymorphism, Genetic; Risk Factors

The human angiotensinogen (AGT) is a promising candidate gene for evaluating susceptibility to essential hypertension (EH). We aimed to assess the association of the variants of AGT gene and the extent of risk involved in developing EH.. A case-control study was designed to compare 279 hypertensive patients with 200 normotensive subjects. The frequency distribution of M235T and T174M polymorphisms of AGT gene was assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. A haplotype analysis was done to determine the risk conferred by the combination of alleles of the two polymorphisms for EH.. The genotype distribution of the T174M variant differed significantly between hypertensives and normotensives, whereas genotypes of M235T variant did not show such difference. For M235T, MM genotype conferred an increase in risk for hypertension in women (odds ratios (OR) = 2.82; 95% confidence interval (CI) = 1.22-6.49). For the variant T174M, the TM genotype frequency was elevated in hypertensive females (36.5%) as compared to controls (18.8 %; P = .034). The 174M allele was more prevalent among female hypertensives than among female controls (0.20 vs. 0.12; P = .059). The haplotype analysis showed a significant association for the haplotypes of paired markers (M235 and 174M) with a χ(2) value of 8.037 (P = .045).. Our findings suggest that the polymorphic variants of AGT gene-M235T and T174M-show association with hypertension.

Topics: Adult; Aged; Angiotensinogen; Case-Control Studies; Female; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Sex Distribution

We investigated the effects of dual renin-angiotensin system (RAS) blockade on angiotensin-converting enzyme-2 (Ace2) expression, hypertension, and renal proximal tubular cell (RPTC) apoptosis in type 1 diabetic Akita angiotensinogen (Agt)-transgenic (Tg) mice that specifically overexpress Agt in their RPTCs. Adult (11 wk old) male Akita and Akita Agt-Tg mice were treated with two RAS blockers (ANG II receptor type 1 blocker losartan, 30 mg·kg(-1)·day(-1)) and angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg·kg(-1)·day(-1)) in drinking water. Same-age non-Akita littermates and Agt-Tg mice served as controls. Blood pressure, blood glucose, and albuminuria were monitored weekly. The animals were euthanized at age 16 wk. The left kidneys were processed for immunohistochemistry and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess gene and protein expression. Urinary ANG II and ANG 1-7 were quantified by ELISA. RAS blockade normalized renal Ace2 expression and urinary ANG 1-7 levels (both of which were low in untreated Akita and Akita Agt-Tg), prevented hypertension, albuminuria, tubulointerstitial fibrosis and tubular apoptosis, and inhibited profibrotic and proapoptotic gene expression in RPTCs of Akita and Akita Agt-Tg mice compared with non-Akita controls. Our results demonstrate the effectiveness of RAS blockade in preventing intrarenal RAS activation, hypertension, and nephropathy progression in diabetes and support the important role of intrarenal Ace2 expression in modulating hypertension and renal injury in diabetes.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Gene Expression; Hypertension; Kidney; Kidney Tubules, Proximal; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nephrosclerosis; Peptidyl-Dipeptidase A; Perindopril; Rats; Renin-Angiotensin System; Transgenes

Topics: Angiotensinogen; Blood Pressure; DNA; Endothelium, Vascular; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Vascular Stiffness

The factors which contribute to an exaggerated blood pressure response (EBPR) during the exercise treadmill test (ETT) are not wholly understood. The association between the insertion/deletion polymorphisms of the angiotensin-converting enzyme (ACE) and M235T of the angiotensinogen with EBPR during ETT still remains unstudied. To identify and compare the risk factors for hypertension between normotensive subjects with EBPR and those who exhibit a normal curve of blood pressure (BP) during ETT. In a series of EBPR cases from a historical cohort of normotensive individuals, a univariate analysis was performed to estimate the association of the studied factors with BP behavior during ETT. Additionally, logistic multivariate regression was conducted to analyze the joint effects of the variables. P-values above 0.05 were considered statistically significant. From a total of 10,027 analyzed examinations, only 219 met the criteria employed to define EBPR, which resulted in a prevalence of 12.6%. For the systolic component of the BP, hyperreactive subjects displayed a mean age and body mass index (BMI) significantly higher than the others (P=0.002 and <0.001, respectively). No association was observed between the polymorphisms cited above and EBPR. An analysis of the joint effect of variables has indicated that only age (P< 0.001) and BMI (P=0.001) were specifically associated with systolic BP during exercise. Age and BMI were the only factors that independently influenced EBPR during ETT.

Topics: Adolescent; Adult; Aged; Angiotensinogen; Blood Pressure; Cohort Studies; Exercise Test; Female; Genetic Association Studies; Hemodynamics; Humans; Hypertension; INDEL Mutation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; Young Adult

The angiotensinogen gene locus has been associated with essential hypertension in most populations analyzed to date. Increased plasma angiotensinogen levels have been proposed as an underlying cause of essential hypertension in whites; however, differences in the genetic regulation of plasma angiotensinogen levels have also been reported for other populations. The aim of this study was to analyze the relationship between angiotensinogen gene polymorphisms and haplotypes with plasma angiotensinogen levels and the risk of essential hypertension in the Mexican population. We genotyped 9 angiotensinogen gene polymorphisms in 706 individuals. Four polymorphisms, A-6, C4072, C6309, and G12775, were associated with increased risk, and the strongest association was found for the C6309 allele (χ(2)=23.9; P=0.0000009), which resulted in an odds ratio of 3.0 (95% CI: 1.8-4.9; P=0.000006) in the recessive model. Two polymorphisms, A-20C (P=0.003) and C3389T (P=0.0001), were associated with increased plasma angiotensinogen levels but did not show association with essential hypertension. The haplotypes H1 (χ(2)=8.1; P=0.004) and H5 (χ(2)=5.1; P=0.02) were associated with essential hypertension. Using phylogenetic analysis, we found that haplotypes 1 and 5 are the human ancestral haplotypes. Our results suggest that the positive association between angiotensinogen gene polymorphisms and haplotypes with essential hypertension is not simply explained by an increase in plasma angiotensinogen concentration. Complex interactions between risk alleles suggest that these haplotypes act as "superalleles."

Topics: Aged; Aged, 80 and over; Alleles; American Indian or Alaska Native; Angiotensinogen; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Male; Mexico; Phenotype; Phylogeny; Polymorphism, Single Nucleotide; Risk Factors

The role of proximal tubule (PT) angiotensinogen (AGT) in modulating blood pressure has previously been examined using mice expressing PT human AGT and human renin, or rat AGT. These animals are hypertensive; however, the question remains whether alterations in mouse PT AGT alone affects arterial pressure.. Mouse AGT cDNA was knocked-in to the endogenous kidney androgen protein (KAP) gene using an internal ribosomal entry site (IRES)-based strategy.. The KAP-mAGT animals showed kidney-specific KAP-AGT mRNA expression; renal in situ hybridization detected KAP-AGT mRNA only in PT. Urinary AGT was markedly increased in KAP-mAGT mice. On a high Na diet, radiotelemetric arterial pressure showed a systolic pressure elevation; no significant difference in arterial pressure was observed on a normal diet. Plasma renin concentration (PRC) was reduced in KAP-mAGT animals given a high Na diet, but was not different between mouse lines during normal Na intake. Plasma AGT concentration was not altered by overexpression of PT mouse AGT.. In summary, PT overexpression of mouse AGT leads to salt-sensitive hypertension without recruitment of the systemic renin-angiotensin system.

Topics: Angiotensinogen; Animals; Blood Pressure; Chimera; Disease Models, Animal; Female; Gene Knock-In Techniques; Hypertension; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Renin; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride, Dietary

Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients.

Topics: Adult; Aged; Angiotensinogen; Cholesterol; Coronary Artery Disease; Egypt; Female; Genetic Predisposition to Disease; Humans; Hypertension; Lipoproteins, LDL; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Smoking; Triglycerides

The carboxyl terminal-extended form of angiotensin I, proangotensin-12, was recently identified in rat tissues including the small intestine, cardiac ventricles, and kidneys. Single administration of proangiotensin-12 exerts vasoconstrictor and pressor effects, probably by conversion to angiotensin II; however, there are currently no data available about the subacute effects of proangiotensin-12. In the present study, we examined the effects of prolonged infusion of proangiotensin-12 in conscious rats. Continuous, subcutaneous infusion of 240 pmol/kg/min of proangiotensin-12 gradually elevated blood pressure over 14 days, as did the same dose of angiotensin II. The pressor effects of proangiotensin-12 were abolished by oral administration of losartan, an angiotensin II type 1 receptor blocker, or perindopril, an angiotensin converting enzyme (ACE) inhibitor. Meanwhile, angiotensin II-induced elevation of blood pressure was inhibited by losartan but not by perindopril. Both the plasma aldosterone level and heart weight/body weight ratio were increased by the prolonged infusion of proangiotensin-12, but these increases were attenuated by losartan and perindopril. The present results suggest that proangiotensin-12 infused continuously over 14 days exerts pressor effects accompanied with the elevation of plasma aldosterone and cardiac hypertrophy in an ACE- and angiotensin II type 1 receptor-dependent manner.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Cardiomegaly; Heart; Hypertension; Infusions, Subcutaneous; Male; Myocardium; Organ Size; Peptide Fragments; Random Allocation; Rats; Rats, Wistar; Time Factors; Vasoconstrictor Agents; Weight Gain

Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H(2) O(2) ) contribute to hypertension. We examined whether H(2) O(2) mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II).. Ang II (200 ng·kg(-1) ·min(-1) ) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg(-1) ·day(-1) ) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H(2) O(2) , angiotensin AT(1) receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H(2) O(2) and angiotensinogen were also measured.. Ang II increased H(2) O(2) , AT(1) receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H(2) O(2) levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT(1) receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H(2) O(2) levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen.. The renal medulla is a major target for Ang II-induced redox dysfunction. H(2) O(2) appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H(2) O(2) levels may provide future grounds for the treatment of hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Biomarkers; Catalase; Gene Expression Regulation; Hydrogen Peroxide; Hypertension; Kidney Diseases; Kidney Medulla; Male; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases; NF-kappa B; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Evidence of endogenous angiotensin-(1-12) [Ang-(1-12)] may necessitate revision of the accepted view that Ang I is the immediate peptide product derived from the precursor protein angiotensinogen. As the processing of this peptide has not been fully elucidated, we characterized Ang-(1-12) metabolism in the serum and kidney of the mRen2.Lewis rat, a model of high circulating renin and ACE expression. A sensitive HPLC-based method to detect the metabolism ex vivo of low concentrations of (125)I-labeled Ang-(1-12) was utilized. Ang-(1-12) processing to serum did not reveal the participation of renin; however, serum ACE readily converted Ang-(1-12) to Ang I with subsequent metabolism to Ang II. Ang I and Ang II forming activities for serum ACE were 102±4 and 104±3 fmol/ml/min serum (n=3), respectively, and both products were abolished by the potent ACE inhibitor lisinopril. The metabolism of Ang-(1-12) in renal cortical membranes also revealed the formation of Ang I; however, the main products were Ang-(1-7) and Ang-(1-4) at 129±9 and 310±12 fmol/mg/min protein (n=4), respectively. Neprilysin inhibition abolished these products and substantially reduced the overall metabolism of Ang-(1-12). Incubation of Ang-(1-12) with either human or mouse neprilysin revealed identical products. We conclude that endogenous Ang-(1-12) may contribute to the expression of biologically active angiotensins through a renin-independent pathway. The preferred route for Ang-(1-12) metabolism likely reflects the relative tissue content of ACE and neprilysin.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Hypertension; Kidney; Lisinopril; Male; Neprilysin; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Lew; Renin

The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor short hairpin RNA was used to knockdown (pro)renin receptor expression in the brain of nontransgenic normotensive and human renin-angiotensinogen double-transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor, and vasopressin mRNA levels. Plasma vasopressin levels were determined by ELISA. Double-transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor short-hairpin RNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared with the control virus treatment in double-transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double-transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease in sympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with downregulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice.

Topics: Angiotensin II; Angiotensinogen; Animals; Baroreflex; Blood Pressure; Blotting, Western; Brain; Cell Line, Tumor; Humans; Hypertension; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Prorenin Receptor; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Vasopressins

A single-nucleotide polymorphism (C/A) located within an E-box at the -20 position of the human angiotensinogen (AGT) promoter may regulate transcriptional activation through differential recruitment of the transcription factors upstream stimulatory factor (USF) 1 and 2. To study the contribution of USF1 on AGT gene expression, mice carrying a (-20C) human AGT (hAGT) transgene were bred with mice harboring a USF1 gene trap allele designed to knock down USF1 expression. USF1 mRNA was reduced relative to controls in liver (9 ± 1%), perigenital adipose (16 ± 3%), kidney (17 ± 1%), and brain (34 ± 2%) in double-transgenic mice. This decrease was confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation analyses revealed a decrease in USF1, with retention of USF2 binding at the hAGT promoter in the liver of male mice. hAGT expression was reduced in the liver and other tissues of female but not male mice. The decrease in endogenous AGT expression was insufficient to alter systolic blood pressure at baseline but caused reduced systolic blood pressure in female USF1 gene trap mice fed a high-fat diet. Treatment of USF1 knockdown males with intravenous adenoviral short hairpin RNA targeting USF2 resulted in reduced expression of USF1, USF2, and hAGT protein. Our data from chromatin immunoprecipitation assays suggests that this decrease in hAGT is attributed to decreased USF2 binding to the hAGT promoter. In conclusion, both USF1 and USF2 are essential for AGT transcriptional regulation, and distinct sex-specific and tissue-specific mechanisms are involved in the activities of these transcription factors in vivo.

Topics: Angiotensinogen; Animals; Blood Pressure; Blotting, Western; Chromatin Immunoprecipitation; Diet, High-Fat; Dietary Fats; Electrophoretic Mobility Shift Assay; Female; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Hypertension; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Binding; RNA Interference; Sex Factors; Upstream Stimulatory Factors

The risk conferred by the variants and haplotypes of single nucleotide polymorphisms (SNPs) at human angiotensinogen (AGT) gene to essential hypertension (EHT) have been described in several populations with variations in the results attributed to their ethnicity. We attempted to evaluate the risk of -217G>A, -152G>A, -20A>C, -6G>A, T174M, M235T and 15241A>G polymorphisms at AGT locus along with the analyses of haplotype and epistatic interactions in causing susceptibility to EHT.. Two-hundred and forty-nine hypertensives and 248 controls were genotyped for the selected markers.. Study of demographic parameters revealed significant association of obesity, positive family history and non-vegetarian diet habit, suggesting elevated risk of the condition when associated with these parameters. Significantly high risk for males with AA genotype of -217G>A polymorphism was observed for developing EHT (p = .07). Males with -217A (p = .01) showed a two-fold higher risk for EHT. Markers -217G>A and -6G>A were in strong linkage disequilibrium in patients as compared to controls. Strong epistatic interactions were found between -6G>A, M235T and -217G>A markers, supporting the synergistic effect between them leading to EHT.. Our findings suggest that -217A variant is significantly associated with the risk for EHT in males. Further studies on the functional role of the marker -217 are recommended for understanding the cause of association with EHT.

Topics: Angiotensinogen; Case-Control Studies; Epistasis, Genetic; Female; Gene Frequency; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Multifactor Dimensionality Reduction; Polymorphism, Single Nucleotide; Risk Factors

Topics: Angiotensinogen; Animals; Female; Hypertension; Kidney Tubules, Proximal; Male; Sodium Chloride, Dietary

We investigated the impact of heterogeneous nuclear ribonucleoprotein F (hnRNP F) overexpression on angiotensinogen (Agt) gene expression, hypertension, and renal proximal tubular cell (RPTC) injury in high-glucose milieu both in vivo and in vitro. Diabetic Akita transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs were created, and the effects on systemic hypertension, Agt gene expression, renal hypertrophy, and interstitial fibrosis were studied. We also examined immortalized rat RPTCs stably transfected with control plasmid or plasmid containing hnRNP F cDNA in vitro. The results showed that hnRNP F overexpression attenuated systemic hypertension, suppressed Agt and transforming growth factor-β1 (TGF-β1) gene expression, and reduced urinary Agt and angiotensin II levels, renal hypertrophy, and glomerulotubular fibrosis in Akita hnRNP F-Tg mice. In vitro, hnRNP F overexpression prevented the high-glucose stimulation of Agt and TGF-β1 mRNA expression and cellular hypertrophy in RPTCs. These data suggest that hnRNP F plays a modulatory role and can ameliorate hypertension, renal hypertrophy, and interstitial fibrosis in diabetes. The underlying mechanism is mediated, at least in part, via the suppression of intrarenal Agt gene expression in vivo. hnRNP F may be a potential target in the treatment of hypertension and kidney injury in diabetes.

Topics: Angiotensinogen; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibrosis; Gene Expression; Heterogeneous-Nuclear Ribonucleoprotein Group F-H; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Renin-Angiotensin System; Transforming Growth Factor beta1

Increases in plasma angiotensinogen (Ang-N) due to genetic polymorphisms or pharmacological stimuli like estrogen have been associated with a blood pressure (BP) rise, increased salt sensitivity and cardiovascular risk. The relationship between Ang-N, the resetting of the renin-angiotensin system, and BP still remains unclear. Angiotensin (Ang) II-induced genetic hypertension should respond to lisinopril treatment.. A new transgenic rat line (TGR) with hepatic overexpression of native (rat) Ang-N was established to study high plasma Ang-N. The transgene contained a mutation producing Val(5)-Ang-II, which was measured separately from nontransgenic Ile-Ang-II in plasma and renal tissue.. Male homozygous TGR had increased plasma Ang-N (~20-fold), systolic BP (ΔBP+26 mmHg), renin activity (~2-fold), renin activity/concentration (5-fold), total Ang-II (~2-fold, kidney 1.7-fold) but decreased plasma renin concentrations (-46%, kidney -85%) and Ile(5)-Ang-I and II (-93%, -94%) vs. controls. Heterozygous TGR exhibited ~10-fold higher plasma Ang-N and 17 mmHg ΔBP. Lisinopril decreased their SBP (-23 vs. -13 mmHg in controls), kidney Ang-II/I (~3-fold vs. ~2-fold) and Ile(5)-Ang-II (-70 vs. -40%), and increased kidney renin and Ile(5)-Ang-I (>2.5-fold vs. <2.5-fold). Kidney Ang-II remained higher and renin lower in TGR compared with controls.. High plasma Ang-N increases plasma and kidney Ang-II levels, and amplifies the plasma and renal Ang-II response to a given change in renal renin secretion. This enzyme-kinetic amplification dominates over the Ang-II mediated feedback reduction of renin secretion. High Ang-N levels thus facilitate hypertension via small increases of Ang II and may influence the effectiveness of renin-angiotensin system inhibitors.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Feedback, Physiological; Genotype; Hypertension; Kidney; Lisinopril; Male; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System

The intrarenal renin-angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin-angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females.. This study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)-dependent hypertension and high-salt (HS) diet.. Male and female Sprague-Dawley rats were divided into 5 groups for each sex: Normal-salt control, HS diet (8% NaCl), Ang II-infused (80 ng/min), Ang II-infused plus HS diet, and Ang II-infused plus HS diet and treatment with the Ang II receptor blocker, candesartan (25 mg/L in the drinking water). Rats were evaluated for systolic blood pressure (SBP), kidney AGT mRNA expression, urinary AGT excretion, and proteinuria at different time points during a 14-day protocol.. Both male and female rats exhibited similar increases in urinary AGT, with increases in SBP during chronic Ang II infusion. HS diet greatly exacerbated the urinary AGT excretion in Ang II-infused rats; males had a 9-fold increase over Ang II alone and females had a 2.5-fold increase. Male rats displayed salt-sensitive SBP increases during Ang II infusion and HS diet, and female rats did not. In the kidney cortex, males displayed greater AGT gene expression than females during all treatments. During Ang II infusion, both sexes exhibited increases in AGT gene message compared with same-sex controls. In addition, HS diet combined with Ang II infusion exacerbated the proteinuria in both sexes. Concomitant Ang II receptor blocker treatment during Ang II infusion and HS diet decreased SBP and urinary AGT similarly in both sexes; however, the decrease in proteinuria was greater in the females.. During Ang II-dependent hypertension and HS diet, higher intrarenal renin-angiotensin system activation in males, as reflected by higher AGT gene expression and urinary excretion, indicates a mechanism for greater progression of high blood pressure and might explain the sex disparity in development of salt-sensitive hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension; Kidney; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sex Characteristics; Sex Factors; Sodium Chloride, Dietary

Previous studies have demonstrated that urinary angiotensinogen excretion, a biomarker of the intrarenal renin-angiotensin system activity, is associated with clinic blood pressure (BP). In the present study, we investigated the determinants of urinary angiotensinogen excretion and its associations with ambulatory BP.. The study participants were suspected hypertensive patients being off antihypertensive medication for at least 2 weeks and referred to our hypertension clinic for 24-h ambulatory BP monitoring. Ambulatory hypertension was defined as a 24-h BP of at least 130  mmHg systolic or 80  mmHg diastolic. We collected a first morning urine sample for the measurement of angiotensinogen by ELISA kits.. The 446 participants (mean age 51.7 years) included 218 (48.9%) men, and 275 (61.7%) patients had ambulatory hypertension. In addition to age and sex, 24-h urinary sodium excretion was an independent determinant of urinary angiotensinogen-to-creatinine ratio (P = 0.0008). Urinary angiotensinogen-to-creatinine ratio was 34% (P = 0.04) and 82% (P ≤ 0.0001) higher in tertiles 2 and 3 of 24-h urinary sodium excretion, respectively, than in tertile 1. In multivariate analyses, urinary angiotensinogen-to-creatinine ratio was significantly and positively associated with clinic and ambulatory BP (P ≤ 0.02) and the prevalence of ambulatory hypertension [odds ratio (95% confidence interval) associated with two-time increase, 1.24 (1.09-1.39); P = 0.0007].. Urinary angiotensinogen excretion is higher with greater urinary sodium excretion, and is associated with clinic and ambulatory BP.

Topics: Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Creatinine; Female; Humans; Hypertension; Male; Middle Aged

ANG II-stimulated production of reactive oxygen species (ROS) through NADPH oxidase is suggested to activate MAPK pathways, which are implicated in neurally mediated pressor effects of ANG II. Emerging evidence suggests that ANG-(1-7) up regulates MAPK phosphatases to reduce MAPK signaling and attenuate actions of ANG II. Whether angiotensin peptides participate in long-term regulation of these systems in the brain is not known. Therefore, we determined tissue and mitochondrial ROS, as well as expression and activity of MAPK phosphatase-1 (MKP-1) in brain dorsal medullary tissue of hypertensive transgenic (mRen2)27 rats exhibiting higher ANG II/ANG-(1-7) tone or hypotensive transgenic rats with targeted decreased glial expression of angiotensinogen, ASrAOGEN (AS) exhibiting lower ANG II/ANG-(1-7) tone compared with normotensive Sprague-Dawley (SD) rats that serve as the control strain. Transgenic (mRen2)27 rats showed higher medullary tissue NADPH oxidase activity and dihydroethidium fluorescence in isolated mitochondria vs. SD or AS rats. Mitochondrial uncoupling protein 2 was lower in AS and unchanged in (mRen2)27 compared with SD rats. MKP-1 mRNA and protein expression were higher in AS and unchanged in (mRen2)27 compared with SD rats. AS rats also had lower phosphorylated ERK1/2 and JNK consistent with higher MKP-1 activity. Thus, an altered brain renin-angiotensin system influences oxidative stress status and regulates MKP-1 expression. However, there is a dissociation between these effects and the hemodynamic profiles. Higher ROS was associated with hypertension in (mRen2)27 and normal MKP-1, whereas the higher MKP-1 was associated with hypotension in AS, where ROS was normal relative to SD rats.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Dual Specificity Phosphatase 1; Gene Expression Regulation; Hypertension; Ion Channels; JNK Mitogen-Activated Protein Kinases; Male; Medulla Oblongata; Mitochondria; Mitochondrial Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidases; Oligonucleotides, Antisense; Oxidative Stress; Peptide Fragments; Phosphorylation; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reactive Oxygen Species; Renin; Renin-Angiotensin System; Signal Transduction; Uncoupling Protein 2

Visit-to-visit blood pressure (BP) variability has been reported to be a major risk for cardiovascular events. Renin angiotensin system (RAS) gene polymorphisms are reportedly genetic risk factors for cardiovascular diseases and arterial stiffness. In this study, we aimed to reveal the relationship between visit-to-visit BP variability and RAS gene polymorphisms.. Study subjects included 427 essential hypertension patients from the Non-Invasive Atherosclerotic Evaluation in Hypertension study cohort, whose BP was measured during at least six outpatient visits. We analyzed the correlation between visit-to-visit variability in systolic BP (SBP) and RAS gene polymorphisms.. We identified angiotensinogen M235T, angiotensin II type 1 receptor A1166C, and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Only ACE I/D polymorphisms were correlated with variability in diastolic BP; no gene polymorphisms were correlated with variability in SBP.. RAS gene polymorphisms, especially ACE I/D polymorphisms, might genetically influence the visit-to-visit BP variability in hypertensive patients.

Topics: Analysis of Variance; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Chi-Square Distribution; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Office Visits; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Genetic; Predictive Value of Tests; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Previous studies demonstrated that diet-induced obesity increased plasma angiotensin II concentrations and elevated systolic blood pressures in male mice. Adipocytes express angiotensinogen and secrete angiotensin peptides. We hypothesize that adipocyte-derived angiotensin II mediates obesity-induced increases in systolic blood pressure in male high fat-fed C57BL/6 mice. Systolic blood pressure was measured by radiotelemetry during week 16 of low-fat or high-fat feeding in Agt(fl/fl) and adipocyte angiotensinogen-deficient mice (Agt(aP2)). Adipocyte angiotensinogen deficiency had no effect on diet-induced obesity. Basal 24-hour systolic blood pressure was not different in low fat-fed Agt(fl/fl) compared with Agt(aP2) mice (124 ± 3 versus 128 ± 3 mm Hg, respectively). In Agt(fl/fl) mice, high-fat feeding significantly increased systolic blood pressure (24 hours; 134 ± 2 mm Hg; P<0.05). In contrast, high fat-fed Agt(aP2) mice did not exhibit an increase in systolic blood pressure (126 ± 2 mm Hg). Plasma angiotensin II concentrations were increased by high-fat feeding in Agt(fl/fl) mice (low fat, 32 ± 14; high fat, 219 ± 58 pg/mL; P<0.05). In contrast, high fat-fed Agt(aP2) mice did not exhibit elevated plasma angiotensin II concentrations (high fat, 18 ± 7 pg/mL). Similarly, adipose tissue concentrations of angiotensin II were significantly decreased in low fat- and high fat-fed Agt(aP2) mice compared with controls. In conclusion, adipocyte angiotensinogen deficiency prevented high fat-induced elevations in plasma angiotensin II concentrations and systolic blood pressure. These results suggest that adipose tissue serves as a major source of angiotensin II in the development of obesity hypertension.

Topics: Adipocytes; Adipose Tissue; Angiotensinogen; Animals; Blood Pressure; Diet; Heart Rate; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity

Topics: Adipocytes; Angiotensinogen; Animals; Hypertension; Male; Obesity

Hypertension ranks among the most important disease challenges on a global scale. Here, a novel hypothesis is presented which implicates angiotensinogen, i.e. the precursor protein for the hypertensive peptide angiotensin II, as a key culprit in the pathogenesis of hypertension. This hypothesis more precisely entails that intracellular angiotensinogen binds and thereby inactivates the retinoblastoma tumor suppressor protein (RB), consequently leading to an inflammatory and hyperproliferative state that significantly contributes to pathologically increasing blood pressure. Accordingly, a conceivable antihypertensive strategy could comprise RB-derived compounds that neutralize angiotensinogen.

Topics: Angiotensinogen; Humans; Hypertension; Retinoblastoma; Tumor Suppressor Proteins

Numerous association studies have been involved in studying the angiotensinogen (AGT) variants, AGT plasma levels and relations to cardiovascular diseases, such as hypertension, myocardial infarction, coronary heart disease. To investigate a role of AGT G(-6)A and M235T genetic variants for chronic heart failure (CHF) and advanced atherosclerosis (AA), a total of 240 patients with CHF and 200 patients with AA of the Czech origin were evaluated for the study. The study shows the role of polymorphism AGT G(-6)A in genetic background among advanced atherosclerosis patients and chronic heart failure patients (Pg=0.001). This difference was also observed in comparison of AA patients with subgroup of CHF with dilated cardiomyopathy (Pg=0.02; Pa=0.009), and ischemic heart disease (Pg=0.007). The greatest difference between triple-vessel disease and chronic heart failure groups was observed in frequency of GT haplotype (P<0.001) and GGMT associated genotype (P<0.001). Retrospectively, we found the same trend when the subgroups of CHF were compared to AA group (AA vs. IHD with CHF P<0.001; AA vs. DCM P<0.001). These results suggest AGT genetic variants as a risk factor for chronic heart failure compared to advanced atherosclerosis disease without heart failure, with a strong difference between IHD patients and chronic heart failure patients with ischemic heart disease, especially in haplotypes and associated genotypes.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Atherosclerosis; Coronary Disease; Female; Gene Frequency; Genotype; Haplotypes; Heart Failure; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients.. In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP ≥160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing.. Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4 mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro)renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend <0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis.. This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Female; Haplotypes; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Pharmacogenetics; Polymorphism, Single Nucleotide; Prorenin Receptor; Receptors, Cell Surface

The present study examined the inhibitory action of temporary treatment with an angiotensin type 1 (AT(1)) receptor blocker (ARB) on vascular remodeling using hypertensive mice with overexpression of the human renin (hRN) and angiotensinogen (hANG) genes.. hRN/hANG transgenic mice (hRN/hANG-Tg) were treated with an ARB, valsartan, from 4 weeks of age. In some mice, valsartan treatment was stopped at 8 weeks of age (temporary treatment). Inflammatory vascular injury was induced by polyethylene-cuff placement around the femoral artery at the age of 10 weeks.. Compared with wild-type (WT) mice, hRN/hANG-Tg showed higher blood pressure (BP) and enhancement of oxidative stress and medial thickening even before cuff placement. Inflammatory vascular remodeling and oxidative stress after cuff placement were further enhanced in hRN/hANG-Tg. Temporary treatment with valsartan continuously lowered BP even after cessation of administration, and inhibited these changes. In contrast, administration of hydralazine lowered BP to a similar level to that with valsartan, but did not inhibit medial thickening and inflammatory vascular remodeling. In contrast to the valsartan treatment, BP immediately increased to the untreated level after cessation of hydralazine.. These results indicate that temporary ARB treatment leads to prolonged effect of BP lowering and prevents vascular remodeling in hypertensive mice induced by activation of the human renin-angiotensin system. The inhibitory action of valsartan is not due to the BP lowering but is at least in part due to a decrease in oxidative stress and inflammation.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Arteries; Blood Vessels; Disease Models, Animal; Hydralazine; Hypertension; Mice; Mice, Inbred C57BL; NADPH Oxidases; Neointima; Oxidative Stress; Renin; Tetrazoles; Valine; Valsartan

The purpose of this study was to clarify the association of the angiotensinogen gene (AGT) with insulin sensitivity using single nucleotide polymorphism (SNP) and haplotype analyses in a white cohort. A candidate gene association study was conducted in white persons with and without hypertension (N = 449). Seventeen SNPs of the AGT gene and their haplotypes were analyzed for an association with homeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression model accounting for age, sex, body mass index, hypertension status, study site, and sibling relatedness was used to test the hypothesis. Nine of the 17 SNPs were significantly associated with lower HOMA-IR levels. Homozygous minor allele carriers of the most significant SNP, rs2493134 (GG), a surrogate for the gain-of-function mutation rs699 (AGT p.M268T), had significantly lower HOMA-IR levels (P = .0001) than heterozygous or homozygous major allele carriers (AG, AA). Direct genotyping of rs699 in a subset of the population showed similar results, with minor allele carriers exhibiting significantly decreased HOMA-IR levels (P = .003). Haplotype analysis demonstrated that haplotypes rs2493137A|rs5050A|rs3789678G|rs2493134A and rs2004776G|rs11122576A|rs699T|rs6687360G were also significantly associated with HOMA-IR (P = .0009, P = .02), and these results were driven by rs2493134 and rs699. This study confirms an association between the AGT gene and insulin sensitivity in white humans. Haplotype analysis extends this finding and implicates SNPs rs2493134 and rs699 as the most influential. Thus, AGT gene variants, previously shown to be associated with AGT levels, are also associated with insulin sensitivity; suggesting a relationship between the AGT gene, AGT levels, and insulin sensitivity in humans.

Topics: Adult; Alleles; Angiotensinogen; Female; Gene Frequency; Genetic Association Studies; Genotype; Haplotypes; Humans; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Mutation; Polymorphism, Single Nucleotide

Essential hypertension is a complex multifactorial disease caused by interactions between genetic and environmental factors. It is an independent determinant of cardiovascular risk. The main aim of this study was to investigate the possible influence of angiotensinogen M268T polymorphisms on hypertension in two endogamous caste populations of South India. Systolic and diastolic blood pressure, anthropometric variables, and lipid profiles were assessed. Direct sequencing of PCR products was adopted for genotyping. This polymorphism was found to be in Hardy-Weinberg equilibrium in the patients and controls of both populations. Binary odds ratios showed significant association between the M268T polymorphism and hypertension in both populations. Multivariate analysis revealed significant differences in body mass index, chest girth, calf circumference, skinfold measurements, total cholesterol, and triglyceride levels between these genotypes in the Gavara and Vaishya populations. These data further support the hypothesis that hypertension is influenced by the AGT M268T polymorphism.

Topics: Adult; Angiotensinogen; Body Mass Index; Case-Control Studies; Cholesterol; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; India; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Skinfold Thickness; Triglycerides

The hypertensive double-transgenic (dTG) rat strain, expressing human renin and angiotensinogen, develops severe hypertension and organ damage and 50% of individuals die by 7 weeks of age. Here, we characterise a variation of this model in which animals present stable hypertension.. The effect of renin-angiotensin system blockers on blood pressure was determined with adult dTG rats treated with enalapril from 3 to 12 weeks of age. Tissue expression levels of renin and angiotensinogen were determined in dTG rats and rhesus monkeys by quantitative PCR.. Upon withdrawal from enalapril, mean arterial pressure (MAP) rose to 160-180 mmHg, with 95% of the female dTG rats surviving for 6 to 12 months, In Sprague-Dawley (SD) rats and rhesus monkeys, renin mRNA was absent or weakly expressed in most tissues, except for the kidneys and adrenals. In dTG rats, human renin expression was high in many additional tissues. The expression of human angiotensinogen in dTG rats followed a similar tissue pattern to SD and rhesus monkey angiotensinogen. Oral dosing of aliskiren, enalapril or losartan provided a similar maximal reduction in MAP and duration of efficacy in telemetrised dTG rats.. Enalapril-pretreated dTG rats are suitable for long-term MAP monitoring and sequential evaluation of human renin inhibitors.

Topics: Amides; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Female; Fumarates; Gene Expression Regulation; Heart Rate; Humans; Hypertension; Macaca mulatta; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; RNA, Messenger; Tissue Distribution

Silicon is rich in the normal human aorta but decreases with age and the development of atherosclerosis. We hypothesized that soluble silica (Si) and coral sand (CS), as a natural Si-containing material, would suppress high blood pressure (BP) in spontaneously hypertensive rats (SHRs), and clarify the observed antihypertensive mechanism by cell cultures by quantifying messenger RNA expressions in the aorta. In SHR fed diets containing 1% Ca supplemented with CaCO(3) as the control (CT) and CS in a Ca-deficient diet and containing 50 mg/kg Si in the CT diet for 8 weeks, systolic BP was significantly (P < .05) lowered by 18 mm Hg for the Si group and 16 mm Hg for the CS group compared with the control CT group with 207 mm Hg. Magnesium (Mg) uptake by rat aortic smooth muscle cells significantly increased (177%, P < .005) in cells cultured with a physiologic Mg level plus Si compared with those with no Si addition. Furthermore, the increase of systolic BP by the CT diet was significantly suppressed by 17 mm Hg (P < .001) in SHR fed the diet containing Mg along with Si, but not by the Mg-deficient diet with or without Si. Soluble silica and CS treatments suppressed the aortic gene expressions of angiotensinogen and growth factors related to vascular remodeling, whereas, Si stimulated the expression of peroxisome proliferator-activated receptor-γ, the activation of which has anti-inflammatory and antihypertensive effects on vascular cells. These findings suggest that Si reduces hypertension in SHR by stimulating the intracellular Mg uptake and related gene expression in the aorta.

Topics: Angiotensinogen; Animals; Anthozoa; Antihypertensive Agents; Aorta; Blood Pressure; Blood Vessels; Calcium; Cardiovascular System; Cells, Cultured; Dietary Supplements; Gene Expression; Hypertension; Male; PPAR gamma; Rats; Rats, Inbred SHR; RNA, Messenger; Silicon Dioxide

Resistant hypertension, a complex multifactorial hypertensive disease, is triggered by genetic and environmental factors and involves multiple physiological pathways. Single genetic variants may not reveal significant associations with resistant hypertension because their effects may be dependent on gene-gene or gene-environment interactions. We examined the interaction of angiotensin I-converting enzyme (ACE), angiotensinogen (AGT), and endothelial nitric oxide synthase (NOS3) polymorphisms with environmental factors (gender, age, body mass index, glycemia, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, and urinary sodium excretion) in 70 resistant, 80 well-controlled hypertensive patients, and 70 normotensive controls. All subjects were genotyped for ACE insertion/deletion (rs1799752); AGT M235T (rs699), and NOS3 Glu298Asp (rs 1799983). Multifactorial associations were tested using two statistical methods: the traditional parametric method (adjusted logistic regression analysis) and gene-gene and gene-environment interactions evaluated by multifactor dimensionality reduction analyses. While adjusted logistic regression found no significant association between the studied polymorphisms and controlled or resistant hypertension, the multifactor dimensionality reduction analyses showed that carriers of the AGT 235T allele were at increased risk for resistant hypertension, especially if they were older than 50 years. The AGT 235T allele constituted an independent risk factor for resistant hypertension.

Topics: Angiotensinogen; Case-Control Studies; Drug Resistance; Environment; Female; Gene Frequency; Genetic Loci; Genetic Markers; Genotype; Humans; Hypertension; Logistic Models; Male; Middle Aged; Multifactor Dimensionality Reduction; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

Genetic polymorphisms of the renin-angiotensin system (RAS) have been reported to play an important role in the pathogenesis of diabetes mellitus and hypertension. In addition, a close association has been reported between RAS and the progression of both diabetes and hypertension. But the role of RAS on the development of posttransplantation diabetes mellitus (PTDM) is not known. For this purpose we investigated the association of polymorphisms in the genes for angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) with the development of PTDM.. Genotyping for ACE insertion/deletion (I/D) and AGT M235T polymorphisms was performed in 50 patients who underwent renal transplantation during a 5-year period. Group 1 consisted of 23 recipients who developed PTDM and group 2 consisted of 27 recipients that did not have PTDM.. Of 50 patients, 13 (26%) showed the ACE DD, 21 (42%) the ACE ID, and 16 the ACE II genotype. The frequencies of AGT MM, AGT MT, and AGT TT were 0, 54%, and 46%, respectively. Compared with group 2, there were high frequencies of the AGT TT genotype in group 1 recipients (P<.001). In addition the ACE DD genotype was found significantly higher in group 1 patients compared with group 2 patients (P=.001).. The high frequencies of the AGT TT genotype and ACE DD genotype in recipients may contribute to the high prevalence of PTDM. Our data suggest a synergistic effect between the ACE and AGT polymorphism in the risk of PTDM, but to support this theory a larger patient group must be studied.

Topics: Adult; Angiotensinogen; Diabetes Complications; Diabetes Mellitus; Disease Progression; Female; Gene Deletion; Genotype; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Transplantation, Homologous

Angiotensin-converting enzyme inhibitors are widely used antihypertensive drugs with individual response variation. We studied whether interactions of AGT, AGTR1 and ACE2 gene polymorphisms affect this response.. Our study is based on a 3-year field trial with 1831 hypertensive patients prescribed benazepril. Generalized multifactor dimensionality reduction was used to explore interaction models and logistic regressions were used to confirm them.. A two-locus model involving the AGT and ACE2 genes was found in males, the sensitive genotypes showed an odds ratio (OR) of 1.9 (95% CI: 1.3-2.8) when compared with nonsensitive genotypes. Two AGT-AGTR1 models were found in females, with an OR of 3.5 (95% CI: 2.0-5.9) and 3.1 (95% CI: 1.8-5.3).. Gender-specific gene-gene interactions of the AGT, AGTR1 and ACE2 genes were associated with individual variation of response to benazepril. Further studies are needed to confirm this finding.

Topics: Adult; Aged; Angiotensin-Converting Enzyme 2; Angiotensinogen; Antihypertensive Agents; Asian People; Benzazepines; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

It is generally known that risk variants segregate together with a disease within families, but this information has not been used in the existing statistical methods for detecting rare variants. Here we introduce two weighted sum statistics that can apply to either genome-wide association data or resequencing data for identifying rare disease variants: weights calculated based on sibpairs and odd ratios, respectively. We evaluated the two methods via extensive simulations under different disease models. We compared the proposed methods with the weighted sum statistic (WSS) proposed by Madsen and Browning, keeping the same genotyping or resequencing cost. Our methods clearly demonstrate more statistical power than the WSS. In addition, we found that using sibpair information can increase power over using only unrelated samples by more than 40%. We applied our methods to the Framingham Heart Study (FHS) and Wellcome Trust Case Control Consortium (WTCCC) hypertension datasets. Although we did not identify any genes as reaching a genome-wide significance level, we found variants in the candidate gene angiotensinogen significantly associated with hypertension at P = 6.9 × 10(-4), whereas the most significant single SNP association evidence is P = 0.063. We further applied the odds ratio weighted method to the IFIH1 gene for type-1 diabetes in the WTCCC data. Our method yielded a P-value of 4.82 × 10(-4), much more significant than that obtained by haplotype-based methods. We demonstrated that family data are extremely informative in searching for rare variants underlying complex traits, and the odds ratio weighted sum statistic is more efficient than currently existing methods.

Topics: Angiotensinogen; Case-Control Studies; Databases, Genetic; DEAD-box RNA Helicases; Diabetes Mellitus, Type 1; Female; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Hypertension; Interferon-Induced Helicase, IFIH1; Male; Models, Genetic; Models, Statistical; Odds Ratio; Polymorphism, Single Nucleotide; Risk Factors; Siblings

The study objective was to examine the association of hypertension in the Lebanese population with three renin-angiotensin system gene polymorphisms (RAS): angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin-receptor type 1 (AT1R).. A total of 270 subjects (124 hypertensive vs 146 normotensive) were genotyped for ACE insertion (I)/deletion (D), AGT (M235T), and AT(1)R (A1166C) gene polymorphisms by polymerase chain reaction and restriction fragment length polymorphism.. The studied genes showed no deviation from Hardy-Weinberg equilibrium. No association could be reported with the ACE I/D polymorphism, although the D allele frequency was high (77%) in patients. AGT TT genotype prevalence was found to be lower in hypertensive versus normotensive subjects (p<0.0001). AT(1)R CC and AC genotypes were significantly more frequent in hypertensive than normotensive subjects (p<0.0001).. The first conducted study on the RAS gene polymorphisms in Lebanese hypertensive patients demonstrated a possible association of the AGT T and AT(1)R C alleles with hypertension.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Lebanon; Middle Aged; Models, Genetic; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The plasmatic angiotensinogen (AGT) level has been associated with essential hypertension. Linkage analysis has found a relationship between the AGT gene locus and hypertension in the Mexican-American population, but studies have failed to identify genetic variants associated with hypertension or plasma AGT levels. This study analyzes the relationship between polymorphisms in the AGT gene and plasmatic AGT levels in Mexican population.. Nine polymorphisms in AGT gene were genotyped, and plasma AGT level was determined by enzyme-linked immunosorbent assay.. Differences in AGT plasma levels were associated with 2 polymorphisms: T-20G, TT = 25.3 ± 8.3 versus TG + GG = 21.6 ± 8.8 μg/mL; P = 0.008 and C3389T (T174M), CC = 25.8 ± 9.9 versus TC + TT = 20.5 ± 5.4 μg/mL; P = 0.0002. Haplotype 2 was associated with low plasma AGT (-5.1 μg/mL [95% confidence interval: -8.6 to -1.6], P = 0.004) and Haplotype 8 was associated with high plasma AGT (6.5 μg/mL [95% confidence interval: 2.5 to 10.6], P = 0.001). This association remained after adjustment for covariates. A Likelihood Ratio Test for haplotype-phenotype association adjusted for covariates resulted in χ = 38.9, P = 0.0005. The total effect of the haplotypes on plasma AGT level variance was 19.5%. No association was identified between haplotypes and quantitative traits of blood pressure.. Two polymorphisms (T-20G and C3389T) and 2 haplotypes (H2 and H8) showed an association with plasma AGT levels in Mexican population.

Topics: Aged; Angiotensinogen; Blood Pressure; Enzyme-Linked Immunosorbent Assay; Female; Genes; Genetic Association Studies; Genotype; Haplotypes; Humans; Hypertension; Male; Mexico; Obesity; Polymorphism, Single Nucleotide

The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67(phox)-related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia.

Topics: Amides; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Brain Ischemia; Cognition Disorders; Cyclic N-Oxides; Dementia, Vascular; Disease Models, Animal; Fumarates; Hypertension; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Renin; Renin-Angiotensin System; Risk Factors; Spin Labels

Genetic predisposition, including polymorphisms of the renin-angiotensin system (RAS) genes, are among the potential factors that may affect the occurrence of hypertension, anemia, or erythrocytosis as well as transplanted kidney function. However, the association of the RAS genes polymorphism and the kidney transplant outcomes is controversial. The aim of this study was to analyze the association between polymorphic variants of the angiotensin-converting enzyme (insertion/deletion [I/D]), angiotensinogen (M235T), and angiotensin II receptor type 1 (A1166C) genes, and the early and long-term kidney graft outcomes, as well as the prevalence of hypertension, anemia and erythrocytosis after kidney transplantation.. We included 331 consecutive kidney transplant patients performed between 1998 and 2003. Of the total, 87.9% of patients completed a 5-year follow-up. Subjects were genotyped for the I/D, M235T, and A1166C polymorphisms.. None of the examined polymorphism affected early or long-term graft function or was associated with hypertension before or after kidney transplantation. There was no significant difference in genotype distribution between patients with and without posttransplant erythrocytosis. However, posttransplant anemia (PTA) seemed to be significantly more common among kidney recipients with TT and MT than MM angiotensinogen genotypes (35.7% vs 20.7%; P=.03). The T allele was associated with the risk of development of PTA (odds ratio, 2.12; 95% confidence interval, 1.12-3.99; P=.02).. Our results do not support the hypothesis that polymorphism of the genes coding RAS components may by an independent risk factor for the development of interstitial fibrosis/tubular atrophy, posttransplant hypertension, or PTE. Further studies are necessary to investigate the association between angiotensinogen M235T genotypes and PTA.

Topics: Adult; Anemia; Angiotensinogen; Female; Follow-Up Studies; Genetic Association Studies; Graft Survival; Humans; Hypertension; INDEL Mutation; Kidney Transplantation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polycythemia; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

The aim of the present study was to determine whether the eye tissues of arterial hypertensive rats evince expression of angiotensin receptors (AT(1) and AT(2)) as well as the novel Mas receptor, whose endogenous ligand is vasorelaxing Angiotensin (1-7) [Ang (1-7)].. Enucleated eyes from spontaneously hypertensive rats (SHR) and double transgenic rats harbouring human renin and angiotensinogen genes (dTGR) and their normotensive controls were used. Half of the rats were pretreated orally with an Angiotensin II (Ang II) type 1 receptor blocker (ARB). The eyes were snap-frozen in isopentane at -40 degrees and stored at -70 degrees for subsequent reverse transcriptase polymerase chain reaction (RT-PCR) analysis or in vitro autoradiography.. The mRNA expression of AT(1a) and AT(2) as well as the novel Mas receptor was detected in all rat groups, being markedly higher in the retina than in the ciliary body. dTGR had significantly more receptors than SHR, but no direct relation to blood pressure level was seen. According to the autoradiography, treatment with ARB blocked a part of AT(1) receptors but had no clear effect on AT(2) receptors.. The novel Mas receptor was found by RT-PCR in eye tissue for the first time. Its specific ligand, Ang (1-7), may be involved in the regulation of intraocular pressure--as recently demonstrated by us--and in the pathogenesis of retinal diseases as a counter-regulatory component for the vascular and proliferative actions of Ang II. The results suggest that the density of AT(1) receptors in the eye is independent of the blood pressure level of the animal.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Autoradiography; Blood Pressure; Ciliary Body; Gene Expression Regulation; Hypertension; Intraocular Pressure; Male; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin; Retina; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To better understand the relationship between angiotensinogen (AGT) genetic variation and essential hypertension, AGT genotypes and haplotypes were tested for association with hypertensive endophenotypes and essential hypertension.. Two hundred and fifty-six Hypertensive Pathotype (HyperPATH)/Specialized Center of Research (SCOR) cases and 126 controls were genotyped for 24 single-nucleotide polymorphisms (SNPs) in the AGT gene. SNPs and AGT haplotypes were tested for association with plasma AGT, renal plasma flow (RPF), and essential hypertension.. New associations between essential hypertension, plasma AGT, and RPF are reported for alleles -1178G, 6066A, 6152A, 6233C, and 12822C. The maximum odds ratio for association of hypertension and AGT genetic variation was 2.3 [95% confidence interval (CI) 1.5-3.8; P < 0.0003] for allele 6233C. Previous associations for -1074T, -532T, -217A, -6A, and 4072C are confirmed (P < 0.05). Sodium depletion enhances associations between AGT SNPs and plasma AGT. Most individually associated SNPs, including -6A and 4072C, are found on a common complete AGT haplotype, H4 (frequency = 0.09). Individuals with haplotype H4 have significantly higher plasma AGT and reduced RPF (P < 0.003 and P < 0.0002, respectively). Other common haplotypes are not associated with increased plasma AGT levels in this data set despite the presence of the -6A and 4072C alleles, suggesting that AGT haplotype H4 is more predictive of elevated plasma AGT than is -6A or 4072C.. This study demonstrates the importance of analyzing haplotypes in addition to single genotypes in association studies. By demonstrating the dependence of AGT associations on sodium depletion status, it helps to explain previous conflicting association results.

Topics: Adult; Angiotensinogen; Blood Pressure; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Kidney; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Renal Circulation; Sodium

Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT(1)R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9-12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng x kg(-1) x min(-1) for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 +/- 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 +/- 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 +/- 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 +/- 0.07, P < 0.05) or in combination with ANG II (0.80 +/- 0.07, P < 0.05). AT(1)R protein (by WB) was increased by ANG II (1.27 +/- 0.06, P < 0.05) and ACEi (1.17 +/- 0.06, P < 0.05) but not ANG II + ACEi [1.15 +/- 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 +/- 0.23, P < 0.05) and ACEi (1.57 +/- 0.15, P < 0.05), but not ANG II + ACEi (1.10 +/- 0.15, NS). No significant changes were observed in AGT, ACE, or AT(1)R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT(1)R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Disease Models, Animal; Hypertension; Kidney; Lisinopril; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Vasoconstrictor Agents

In order to get insight into possible genetic determinants of antihypertensive drug action, we analysed the relations between polymorphisms of the genes of the renin-angiotensin-aldosterone system and acute effects of ACE inhibition on blood pressure as well as circulating renin and aldosterone levels in hypertensive patients.. A total of 315 hypertensive patients referred for problems in drug treatment were given a single 50 mg dose of captopril. Plasma renin and aldosterone were measured before and 60 min after the drug administration. Four DNA variants, including angiotensin type I receptor (AGTR1) 1166 A/C, angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and AGT -217 G/A, were genotyped in the patients and normotensive men (n = 175). A replication study on the relation between AGTR1 1166 A/C and plasma renin and aldosterone levels was carried out in the 244 hypertensive men of the pharmacogenetic GENRES Study.. Referred hypertensive patients with the AGTR1 CC genotype had higher aldosterone at baseline (P = 0.02) and after 60 min of captopril administration (P = 0.01) compared with the AA genotype. Replicate analysis in the GENRES patients showed a similar trend. When the two studies were combined (315 and 244 patients, respectively), plasma aldosterone level (P = 0.007) as well as aldosterone/renin ratio (P = 0.04) were significantly higher in the CC genotype (n = 13) than in the AA genotype (n = 370). Transfection studies in cultured HEK293 cells indicated that the 1166C allele was associated with higher mRNA levels than the 1166A allele.. The AGTR1 1166C allele when present in homozygous form may be associated with a form of essential hypertension characterized by high plasma aldosterone and low plasma renin levels, possibly due to increased AGTR1 mRNA levels and augmented angiotensin II action.

Topics: Adult; Aldosterone; Alleles; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Captopril; Cohort Studies; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Receptors, Angiotensin; Reference Values; Renin; Renin-Angiotensin System

Hypertension is a known risk factor for renal cell carcinoma (RCC), although the underlying biological mechanisms of its action are unknown. To clarify the role of hypertension in RCC, we examined the risk of RCC in relation to 142 single-nucleotide polymorphisms (SNPs) in eight genes having a role in blood pressure control. We analyzed 777 incident and histologically confirmed RCC cases and 1035 controls who completed an in-person interview as part of a multi-center, hospital-based case-control study in Central Europe. Genotyping was conducted with an Illumina GoldenGate Oligo Pool All assay using germ line DNA. Of the eight genes examined, AGT (angiotensinogen) was most strongly associated with RCC (minimum P-value permutation test = 0.02). Of the 17 AGT tagging SNPs considered, associations were strongest for rs1326889 [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15-1.58] and rs2493137 (OR = 1.31, 95% CI = 1.12-1.54), which are located in the promoter. Stratified analysis revealed that the effects of the AGT SNPs were statistically significant in participants with hypertension or high body mass index (BMI) (> or =25 kg/m(2)), but not in subjects without hypertension and with a normal BMI (<25 kg/m(2)). Also, haplotypes with risk-conferring alleles of markers located in the promoter and intron 1 regions of AGT were significantly associated with RCC compared with the common haplotype in subjects with hypertension or high BMI (global P = 0.003). Our findings suggest that common genetic variants of AGT, particularly those in the promoter, increase RCC risk among subjects who are hypertensive or overweight.

Topics: Adult; Aged; Angiotensinogen; Body Mass Index; Carcinoma, Renal Cell; Case-Control Studies; Female; Haplotypes; Humans; Hypertension; Kidney Neoplasms; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system.. To investigate the effects of the time-course of hypertension over 1) hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate); 2) left ventricular hypertrophy; and 3) local and systemic Renin-angiotensin system of the spontaneously hypertensive rats.. MALE SPONTANEOUSLY HYPERTENSIVE RATS WERE RANDOMIZED INTO TWO GROUPS: young (n=13) and adult (n=12). Hemodynamic signals (blood pressure, heart rate), blood pressure variability (BPV) and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g), by myocyte diameter (mum) and by relative fibrosis area (RFA, %). ACE and ACE2 activities were measured by fluorometry (UF/min), and plasma renin activity (PRA) was assessed by a radioimmunoassay (ng/mL/h). Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU).. The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components.. The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent established end-organ damage is reached.

Topics: Age Factors; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Random Allocation; Rats; Rats, Inbred SHR; Renin-Angiotensin System

Studies of knockout and transgenic mice have demonstrated key roles for genes encoding components of the renin angiotensin system in blood pressure regulation. However, whether polymorphisms in these genes contribute to the cause of essential hypertension in humans is still a matter of debate.. We performed an experiment with dense tagging single-nucleotide polymorphism coverage of 4 genes encoding proteins that control the overall activity of the cascade, namely renin, angiotensinogen, angiotensin-converting enzyme, and angiotensin-converting enzyme 2, in 2 Irish populations. Both clinic and 24-hour ambulatory blood pressure measurements were available from population I (n=387), whereas just clinic blood pressure was measured in population II (n=1024). Of the 23 polymorphisms genotyped, only a single renin gene polymorphism, REN-5312C/T, showed consistent statistically significant associations with elevated diastolic pressures. Carriage of one REN-5312T allele was associated with the following age- and sex-adjusted increments in diastolic pressures (mean [95% CI]): population I, clinic, 1.5 mm Hg (0.3 to 2.8); daytime, 1.4 mm Hg (0.4 to 2.4); night-time, 1.3 mm Hg (0.4 to 2.3), and population II, clinic, 1.1 mm Hg (0.1 to 2.1). Haplotypic analyses and multivariate stepwise regression analyses were in concordance with individual single-nucleotide polymorphism analyses.. The REN-5312T allele had been shown previously to result in increased in vitro expression of the renin gene. We have now shown, in 2 independent populations, that carriage of a REN-5312T allele is associated with elevated diastolic blood pressure. These data provide evidence that renin is an important susceptibility gene for arterial hypertension in whites.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Angiotensin-Converting Enzyme 2; Angiotensinogen; Blood Pressure; Female; Genotype; Haplotypes; Humans; Hypertension; Ireland; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Regression Analysis; Renin; Renin-Angiotensin System; White People

Candidates for coronary artery bypass grafting (CABG) represent a group of patients with well documented, severe coronary artery disease (CAD). Genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) components have been associated with CAD. We examined the association of polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT(1) receptor) with severe CAD in CABG patients.. One hundred and fifty-four CABG patients and 155 non-CAD controls were included in the study. Established PCR methods were used for genotyping of AGT M235T, AGT T174M, AT(1) receptor A1166C, and ACE I/D polymorphisms. Cumulative effect of analysed polymorphisms was assessed by calculation of each individual's RAAS gene score (addition of 0.5 points for each variant allele and then calculating the sum for all four polymorphisms).. No association between AGT M235T, AGT T174M, ACE I/D and AT(1) receptor A1166C polymorphisms and CAD was observed. Within CABG patients, the frequency of homozygous AGT 235TT genotype was higher in hypertensive compared to normotensive CABG patients (21.7% vs. 6.3%, p=0.03). RAAS gene score did not differ between CABG patients and non-CAD controls.. There is no association of the analysed RAAS polymorphisms with severe CAD in CABG patients. However, within these patients, an association was found between AGT 235TT genotype and hypertension.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Case-Control Studies; Coronary Artery Bypass; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System

Transgenic mice that overexpress angiotensinogen, the sole precursor of angiotensins, in their renal proximal tubular cells develop hypertension, albuminuria, and tubular apoptosis. These pathological changes are due to enhanced generation of reactive oxygen species in the proximal tubule cells. Here, we determined whether overexpression of catalase to decrease oxidant injury in the proximal tubular cells could reverse these abnormalities. Double-transgenic mice specifically overexpressing angiotensinogen and catalase in their renal proximal tubular cells were created by cross-breeding the single transgenics. Non-transgenic littermates served as controls. Overexpression of catalase prevented hypertension, albuminuria, tubulointerstitial fibrosis, and tubular apoptosis in the angiotensinogen transgenic mice. Furthermore, the double transgenics had lower reactive oxygen species generation and reduced pro-fibrotic and apoptotic gene expression in the renal proximal tubular cells. Renal angiotensin converting enzyme-2 expression and urinary angiotensin 1-7 levels were downregulated in the single but normal in the double-transgenic mice. Thus, we suggest that the intrarenal renin-angiotensin system and reactive oxygen species generation have an important role in the development of hypertension and renal injury.

Topics: Angiotensinogen; Animals; Apoptosis; Catalase; Gene Expression; Hypertension; Kidney Tubules, Proximal; Mice; Mice, Transgenic; Reactive Oxygen Species; Renin-Angiotensin System

The Bogalusa Heart Study is a long-term study on cardiovascular disease and has followed a biracial (black/white) population from childhood. Risk factor data pertaining to many patients have been collected over 35 years, and the time course of hypertension has been documented by repeated examinations and measurements. Considerable sex and racial differences have been found to be related to cardiovascular disease. Urinary angiotensinogen (UAGT) is a novel biomarker for the intrarenal activity of the renin-angiotensin system in hypertension and kidney disease. We aimed to determine the relationship of UAGT with traditional cardiovascular disease risk factors in asymptomatic young adults in this biracial population.. We recruited 251 individuals and collected a single random spot urine sample from each one. Because UAGT is significantly increased in diabetic patients and the use of antihypertensive drugs affects UAGT levels, we excluded patients who had diabetes, who were receiving antihypertensive treatment, or both. Consequently, 190 participants were included for this analysis.. UAGT levels did not differ with race or sex, but were significantly correlated with SBP (r = +0.23, P = 0.0015) and DBP (r = +0.24, P = 0.0012). Moreover, high correlations were shown in men, especially in black men (SBP, r = +0.85, P = 0.0005 and DBP, r = +0.72, P = 0.0079). Thus, UAGT is correlated with blood pressure in men, even when they do not show overt proteinuria or albuminuria.. The biomarker, UAGT, may facilitate the identification of individuals that are at increased risk for the development of hypertension and early asymptomatic renal disease.

Topics: Adult; Albuminuria; Angiotensinogen; Black People; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Hypotension; Kidney; Longitudinal Studies; Male; Proteinuria; Renin-Angiotensin System; Risk Factors; Urinary Tract; White People

Much remains unknown about the genetic factors that contribute to essential hypertension. The Utah Genetic Reference Project (UGRP) large pedigree collection provides new opportunities to study quantitative relationships between genetic variation, endophenotypes, and blood pressure.. We analyzed the relationship between common single-nucleotide polymorphisms (SNPs) and haplotypes spanning the angiotensinogen (AGT) gene and promoter region, plasma AGT levels, and systolic (SBP) and diastolic blood pressure (DBP) in 424 individuals from 41 two-generation UGRP families.. Plasma AGT levels are significantly correlated among UGRP family members. Correlations are higher for males than for females. Parent-offspring correlations for plasma AGT (0.30) are higher than those for SBP (0.26) and DBP (0.17) (all P values <0.01). The additive heritability (h(2)) for plasma AGT is high (0.74) and substantially exceeds heritability estimates for SBP (0.26) and DBP (0.16) (all P values <0.01). Significant linkage (logarithm of the odds (LOD) >3) is found between six AGT SNPs and plasma AGT. A model that utilizes three AGT haplotype groups produces the best LOD score (5.1) that exceeds the best single SNP LOD score (3.8). Plasma AGT and blood pressure were not significantly correlated.. Plasma AGT levels demonstrate high heritability in 41 UGRP families. Locus-specific heritability estimates for AGT SNPs and haplotypes approach 67%, indicating that variation at AGT accounts for a large percentage of the heritability of plasma AGT. A three-way haplotype model outperforms single SNPs for quantitative linkage analysis to plasma AGT. In these predominantly normotensive individuals, plasma AGT did not correlate significantly with blood pressure.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Female; Genetic Linkage; Haplotypes; Humans; Hypertension; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable

The genes encoding renin-angiotensin system (RAS) components are potent candidate genes in both hypertension and diabetes namely ACE encoding the angiotensin converting enzyme and AGT encoding angiotensinogen. It has been suggested that the insertion/deletion (I/D) polymorphism in intron 16 of ACE gene is associated with ACE levels, and M235T gene polymorphism is associated with plasma AGT levels.. We examined in this report the association between ACE I/D and AGT M235T polymorphisms with hypertension status in Tunisian type 2 diabetic subjects.. Thirty nine hypertensive and 22 normotensive type 2 diabetic Tunisian patients were recruited for this study. The I/D polymorphism of ACE gene was analysed with nested PCR in order to avoid mistyping heterozygous individuals and the M235T polymorphism of AGT gene was analysed using PCR and allele specific restriction.. The distribution of DD, ID and II genotypes did not significantly differ between type 2 diabetic patients with or without hypertension (DD: 49%; ID: 41%; II: 10% vs DD: 36%; ID: 55%; II: 9%, respectively) (chi2=1.06, p=0.58). There was also no significant statistical difference between these two groups for the M235T polymorphism (TT: 20%; MT: 54%; MM: 26% vs TT: 27%; MT: 41%; MM: 32%, respectively) (chi2=0.95, p=0.62).. RAS polymorphisms do not seem to play a role in the development of hypertension in the studied Tunisian type 2 diabetic subjects.

Topics: Aged; Algorithms; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System; Tunisia

There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Genes; Heart; Humans; Hypertension; Male; Mitochondria; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System; Resveratrol; Stilbenes

To investigate the relationship between T704C polymorphism of angiotensinogen (AGT) gene and cerebral hemorrhage and its impact on the levels of blood pressure in Han people in Changsha.. A total of 273 cerebral hemorrhage patients (the cerebral hemorrhage group) and 140 normal controls (the control group) were collected from Jan. 2005 to Jan. 2009. DNA was extracted from their peripheral blood samples. The polymorphism of AGT-T704C was analyzed by SNaPshot and direct DNA sequencing. The possible risk factors of cerebral hemorrhage were investigated at the same time. Each group was divided into 2 subgroups (a high blood pressure subgroup and a normal blood pressure subgroup) according to whether they had essential hypertension. Logistic regression analysis was used to detect the relationship between cerebral hemorrhage and all its possible risk factors and AGT-T704C polymorphism.. The drinking history, coronary heart disease history, essential hypertension history, and blood levels of lipids were shown significant difference between the cerebral hemorrhage group and the control group (P<0.05). Logistic regression analysis showed that hypertension history, systolic blood pressure level, and high density lipoprotein cholesterol level were independent risk factors for cerebral hemorrhage in Han people in Changsha. The genotype C/C, C/T, and T/T frequencies of AGT-T704C polymorphism in the cerebral hemorrhage group and the control group were 0.692, 0.279, 0.029 and 0.629, 0.350, 0.021, respectively. The allele C and T frequencies of AGT-T704C polymorphism in the 2 groups were 0.832, 0.168 and 0.804, 0.196, respectively. The frequencies of all the genotypes and alleles had no significant difference between the 2 groups and their subgroups (P>0.05).. The polymorphism of AGT-T704C may not be associated with cerebral hemorrhage and not related to the levels of lipids and blood pressure in Han people in Changsha. Hypertension history, systolic blood pressure level, and high density lipoprotein cholesterol level are the main risk factors of cerebral hemorrhage in Han people in Changsha.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensinogen; Asian People; Base Sequence; Cerebral Hemorrhage; China; Female; Genotype; Humans; Hypertension; Lipoproteins, HDL; Logistic Models; Male; Middle Aged; Molecular Sequence Data; Polymorphism, Genetic; Risk Factors; Young Adult

The mRen(2).Lewis (mRen2) strain is an ANG II-dependent model of hypertension expressing marked sex differences in blood pressure and tissue injury that also exhibits estrogen and salt sensitivity. Because estrogen and salt influence angiotensinogen (AGT), circulating and renal expression of the protein were assessed in the mRen2 using a sensitive and specific ELISA. Hemizygous female and male mRen2 were placed on normal (1% NaCl, NS)- or high (8% NaCl, HS)-salt diets from 5 to 15 wk of age while a separate NS cohort was ovariectomized (OVX). The OVX mRen2 exhibited higher blood pressure (184 +/- 6 vs. 149 +/- 5 mmHg, n = 6), a 16-fold increase in urinary AGT (uAGT) (0.2 +/- 0.02 vs. 0.01 +/- 0.01 microg x kg(-1) x day(-1), P < 0.01), but no change in proteinuria (PROT). Excretion of AGT was correlated with blood pressure and PROT in the female groups. The HS diet led to higher blood pressure (224 +/- 8 mmHg), a 180-fold increase in uAGT (1.8 +/- 0.2 microg x kg(-1) x day(-1)), and increased PROT (98 +/- 9 vs. 7 +/- 1 mg x kg(-1) x day(-1)). Compared with females, NS males expressed higher excretion of uAGT (3.0 +/- 0.4 microg x kg(-1) x day(-1)) and PROT (32 +/- 5 mg x kg(-1) x day(-1)); both were increased eightfold with HS (uAGT: 23 +/- 3 microg x kg(-1) x day(-1); PROT: 285 +/- 28 mg x kg(-1) x day(-1)) without a change in blood pressure. Although uAGT was markedly higher in the OVX and HS groups, neither renal cortical AGT mRNA or protein expression was increased. Moreover, AGT release in cortical slices was similar for the NS and HS females. We conclude that the increase in uAGT with estrogen depletion or HS likely may be a biomarker for glomerular damage reflecting filtration of the circulating protein in the mRen2.

Topics: Angiotensinogen; Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Estrogens; Female; Hypertension; Kidney; Male; Mice; Ovariectomy; Proteinuria; Rats; Rats, Inbred Lew; Rats, Transgenic; Renin; RNA, Messenger; Sex Factors; Sodium Chloride, Dietary; Time Factors; Up-Regulation

ProAngiotensin-12 (PA12) is the most recent peptide to be identified as a functional component of the renin-angiotensin system (RAS). PA12 is reported to constrict rat coronary arteries and the aorta, dependent upon angiotensin II-converting enzyme 1 (ACE1) and chymase. The current study employed myography to determine the direct vascular effects of PA12 on a range of isolated rat arteries extending from the core to periphery. PA12 significantly constricted the descending thoracic aorta, right and left common carotid arteries, abdominal aorta and superior mesenteric artery, with little effect on the femoral and renal arteries. AngII was found to produce similar responses to PA12 when administered at the same dose. A potency gradient in response to PA12 was clearly apparent, with vessels in closest proximity to the heart responding with the greatest constriction; while constrictive potency was lost further form the heart. Inhibition of ACE1 and chymase both significantly attenuated PA12-induced vasoconstriction, with chymostatin displaying lesser potency. We postulate ACE1 primarily regulates RAS activity within the circulation, while chymase may have an important role in local, tissue-based RAS activity.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Arteries; Captopril; Chymases; Drug Stability; Hypertension; In Vitro Techniques; Male; Oligopeptides; Organ Specificity; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Serine Proteinase Inhibitors; Time Factors; Vasoconstriction; Vasoconstrictor Agents

Macrophages have critical roles in the pathogenesis of atherosclerosis by activating the innate immune system and producing inflammatory cytokines. Accumulating evidence indicates that angiotensin type 1 receptor (AT1R) blockers exert anti-inflammatory effects in inflammatory diseases including atherosclerosis. In this study, we investigated the effect of losartan, an AT1R blocker, on the proinflammatory gene expression induced by bacterial lipopolysaccharide (LPS) in a well-defined in vitro human THP-1 macrophage system. We found that losartan significantly attenuated the LPS-induced expression of proinflammatory genes TNF-alpha, IL-8 and COX-2. However, exogenous angiotensin II (AngII) had no effect on LPS-induced inflammatory signaling despite the expression of AT1R. In addition, losartan did not block LPS-induced IkappaB phosphorylation, which is downstream of Toll-like receptor activation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonists, GW9662 and T0070907, reversed the inhibitory effects of losartan on LPS-induced TNF-alpha and IL-8 expression in THP-1 macrophages. These observations suggest that losartan inhibits LPS-induced proinflammatory gene expression in macrophages by activating the PPARgamma pathway rather than by the competitive inhibition of AT1R binding to AngII.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Atherosclerosis; Cell Line; Gene Expression; Humans; Hypertension; I-kappa B Proteins; Inflammation; Lipopolysaccharides; Losartan; Macrophages; Monocytes; Phosphorylation; PPAR gamma; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Signal Transduction

Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype.. Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates.. Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations.. We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.

Topics: Adult; Angiotensinogen; Blood Pressure Determination; DNA Mutational Analysis; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Netherlands; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Risk Factors

Preeclampsia is a debilitating disorder affecting approximately 3% of pregnant women in the Western world. Although inconclusive, current evidence suggests that the renin-angiotensin system may be involved in hypertension. Therefore, our objective was to determine whether the genes for placental renin (REN) and maternal angiotensinogen (AGT) interact to influence the risk of preeclampsia.. Three haplotype-tagging SNPs (htSNPs) covering REN (rs5705, rs1464818, and rs3795575) and another three covering AGT (rs2148582, rs2478545 and rs943580) were genotyped in 99 mother-father-child triads of preeclampsia pregnancies. We estimated relative risks (RR) conferred by maternal AGT and fetal REN haplotypes using HAPLIN, a statistical software designed to detect multi-marker transmission distortion among triads. To assess a combined effect of maternal AGT and fetal REN haplotypes, the preeclamptic triads were first stratified by presence/absence of maternal AGT haplotype C-T-A and tested for an effect of fetal REN across these strata.. We found evidence that mothers carrying the most frequent AGT haplotype, C-T-A, had a reduced risk of preeclampsia (RR of 0.4, 95% CI = 0.2-0.8 for heterozygotes and 0.6, 95% CI = 0.2-1.5 for homozygotes). Mothers homozygous for AGT haplotypes t-c-g and C-c-g appeared to have a higher risk, but only the former was statistically significant. We found only weak evidence of an overall effect of fetal REN haplotypes and no support for our hypothesis that an effect of REN depended on whether the mother carried the C-T-A haplotype of AGT (p = 0.33).. Our findings indicate that the mother's AGT haplotypes affect her risk for developing preeclampsia. However, this risk is not influenced by fetal REN haplotypes.

Topics: Angiotensinogen; Child; Female; Fetus; Gene Expression; Genes; Genotype; Haplotypes; Heterozygote; Homozygote; Humans; Hypertension; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Regression Analysis; Renin; Renin-Angiotensin System; Risk Factors

AGT*M235T polymorphism has been associated with high serum angiotensinogen (AGT) levels, systemic hypertension and cardiac dysfunction (CD).. To test the hypothesis of AGT*M235T polymorphism being associated with the risk of developing cardiac dysfunction (heart failure or asymptomatic left ventricular systolic dysfunction) after acute coronary syndrome (ACS) during hospitalization.. A total of 363 patients (mean age of 62 ± 12 years), of whom 233 (64%) were men and 130 (36%) were women, all from the same cohort and hospitalized for ACS, were studied. Clinical and genetic data from the 117 (32.2%) patients who developed cardiac dysfunction (case group) were compared to those of the 246 (67.8%) who did not develop this condition (control group). The AGT*M235T polymorphism was determined by sequence analysis and was in Hardy-Weinberg equilibrium.. There was a significant difference in the distribution of genotypes among women, with a predominance of the *235MM genotype in the control group (p = 0.001) and of the *235T allele in the case group. In the logistic regression models, the diagnosis of anterior wall myocardial infarction at admission was related to an increased risk of CD in both genders, whereas unstable angina at admission.; absence of the *235T allele; blood glucose <100 mg/dl; use of betablocker; serum creatinine level < 1.5 mg/dl;heart rate range > 60 and < 90 bpm; and current cigarette smoking were related to a lower risk of CD.. This study suggests that the absence of the AGT *235T allele contributes to a reduced risk of cardiac dysfunction after acute coronary syndrome.

Topics: Acute Coronary Syndrome; Adult; Alleles; Angiotensinogen; Case-Control Studies; Echocardiography; Female; Genotype; Humans; Hypertension; Logistic Models; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Young Adult

To explore the role of genetic variants of angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), and angiotensin type 1 receptor (AT1R A1166C) as predictors of diabetes risk and to examine their combined effects on type 2 diabetes mellitus (T2DM) patients.. One hundred and fourteen T2DM patients were compared to 175 healthy controls with similar age and sex.. The genotypic frequencies for all three genes alone were significantly associated with increased risk of developing diabetes. Logistic regression analysis of classic coronary risk factors and the genetic polymorphisms demonstrated that hypertension and ACE DD genotype were the most significant contributors to T2DM. For the renin-angiotensin system (RAS) genes, the risk of T2DM in individuals with one risk genotype was 1.9 (95%CI: 1.1-3.0, p=0.017) higher than those with zero risk genotype. Individuals who carried two risk genotypes had a 4.0 (95%CI 1.7-9.4, p=0.001) times higher risk of T2DM than those who did not carry any risk genotypes of the RAS genes. Most interestingly, the risk of T2DM for individuals with three risk genotypes was 26.2 (95%CI: 5.8-117.9, p<0.001) higher than those with zero risk genotype.. The results of the present study imply that genotyping of renin-angiotensin system genes could become an important part of the clinical process of risk identification for T2DM in Tunisian population.

Topics: Adult; Aged; Angiotensinogen; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Logistic Models; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Tunisia

Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1)} polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using chi square tests. All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism. Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups.

Topics: Adolescent; Adult; Angiotensinogen; Asian People; DNA; Gene Frequency; Genetic Predisposition to Disease; Genotype; Glutathione S-Transferase pi; Humans; Hypertension; Indians, North American; Integrin beta3; Methylenetetrahydrofolate Reductase (NADPH2); Mexico; Middle Aged; Oxidative Stress; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Risk Factors; Thrombophilia; White People; Young Adult

Topics: Angiotensinogen; Blood Pressure; Humans; Hypertension; Phenotype

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Topics: Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Heart Rate; Hyperglycemia; Hyperlipidemias; Hypertension; Leptin; Male; Obesity; Proteinuria; Rats; Rats, Sprague-Dawley

Renin is a rate-limiting enzyme of the renin-angiotensin system and plays a crucial role in the regulation of blood pressure (BP). Angiotensinogen (AGT) is the precursor of potent vasoactive hormone angiotensin II and the AGT gene has been incriminated as a marker for genetic predisposition to essential hypertension (EH) in some ethnic groups. The purpose of the study is to explore the association of a new genetic marker of renin gene, and AGT gene M235T, A-6G, and A-20C polymorphisms and their haplotypes with EH in the Mongolian population. On the basis of the prevalence survey, 243 hypertensives and 258 normotensives who had no blood relationship with each other were selected as subjects. All the subjects were interviewed with questionnaires and their blood specimens were collected. Renin gene insertion/ deletion (I/D) polymorphism was genotyped by PCR-polyacrylamide gel electrophoresis. AGT gene M235T, A-6G, and A-20C polymorphisms were genotyped by a PCR-restriction fragment length polymorphism and single-strand conformation polymorphism. The frequencies of renin genotype DD and allele D in hypertensives (36.21%, 63.79%, respectively) were significantly higher than those in normotensives (29.84%, 57.17%, respectively, P < 0.05). The odds ratios (OR) of renin genotype ID, DD to renin genotype II on hypertension were 1.98 (OR 95% CI 1.08-3.72) and 2.51 (OR 95% CI 1.33-4.88), respectively. There were no significant differences in the distributions of genotypes and alleles for AGT gene M235T, A-6G, and A-20C polymorphisms and all different haplotypes between the two groups. Renin gene I/D polymorphism is associated with EH, whereas AGT gene M235T, A-6G, and A-20C polymorphisms and the haplotypes are not associated with EH in the Mongolian population.

Topics: Adult; Alleles; Angiotensinogen; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; INDEL Mutation; Male; Middle Aged; Mongolia; Polymorphism, Genetic; Renin

After menopause, blood pressure increases in women. However, the underlying mechanisms responsible for postmenopausal hypertension are not completely understood. This study was conducted to determine the role that the renin-angiotensin system (RAS) plays in post-menopausal hypertension. Post-estrous cycling (postmenopausal) spontaneously hypertensive rats or young female controls were treated with losartan, an angiotensin (Ang) II type 1 receptor blocker, for 25 days. Mean arterial pressure was recorded continuously by radiotelemetry. Losartan significantly decreased blood pressure in postmenopausal rats and young female controls but failed to normalize blood pressure in postmenopausal rats to levels found in young controls. Plasma renin activity and plasma angiotensinogen were significantly elevated, and intrarenal Ang II type 1 receptor and renin mRNA expression were significantly downregulated in postmenopausal rats. Therefore, RAS only partially contributes to hypertension in postcycling spontaneously hypertensive rats, whereas hypertension in young females is mediated mainly by the RAS. The data suggest that other mechanisms besides activation of the RAS are likely involved in postmenopausal hypertension.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Blood Pressure; Female; Hypertension; Kidney; Losartan; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Telemetry

Left ventricle hypertrophy (LVH) is main organ complication developing in the course of primary hypertension. Among 'candidates genes' related with development of hypertension as well as LVH; the promoting, but not crucial, influence of (c.704C>T) angiotensinogen (AGT) gene was found. The elevated calcium ions concentration in the cytosol of muscle cells, might be one of the element in the ethiopatomechanism of essential hypertension development. The ATP-related ions pomp--SERCA2A regulates the intracellular calcium concentration. Mutations in the ATP2A2 gene coding the SERCA2A protein, has been associated with elevated calcium level in cardiomyocytes. The aim of the study was to analyze frequency of the M235T (c.704C>T) AGT gene polymorphism. The new mutations in the ATP2A2 gene was searched for in hypertensive patients, independently to the LVH presence in compare to the control group. 157 people participated in the study. Based on the echo-cardiographic examination participants were divided into subgroups: patients with essential hypertension (NT) and patients with NT and LVH. 50 healthy volunteers served as the control group. The frequency of the CC homozygotes, of the M235T (c.704C>T) AGT gene polymorphism, was the highest in the patients with essential hypertension and LVH in compare with patients without LVH (p = 0.67) and control group (p = 0.64). The value of the LVMI was the highest in CC carriers in compare to homozygotes TT (p = 0.33) and CT group (p = 0.66). In homozygotes TT as well as in the carriers of allel T, the elevated blood pressures value was detected. In the exon 15 of ATPA2A gene the new polymorphism A724A (C.2171G>A) was found. only the presence of GG and heterozygotes GA was detected in analyzed group. The frequency of GA genotype was significantly higher in control group vs patients with essential hypertension with (p = 0.05)/or without LVH (p = 0.04). The GA carriers had lower blood pressures values measured in doctor office as well as using ABPM method. The LVM as well as LVMI values were lower in group with mutated genotype GA in compare to GG group (p = 0.107 for LVM; p = 0.154 for LVMI). Results suggest a protective role of the c.2171G>A polymorphism of the ATP2A2 gene against the hypertension as well as LVH development. It seems also that c.704C>T polymorphism of AGT gene does not play crucial role in the essential hypertension development.

Topics: Angiotensinogen; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Mutation; Polymorphism, Genetic; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Hypertension is a well-recognized complication of autosomal recessive polycystic kidney disease (ARPKD). The renin-angiotensin system (RAS) is a key regulator of blood pressure; however, data on the RAS in ARPKD are limited and conflicting, showing both up- and down-regulation. In the current study, we characterized intrarenal and systemic RAS activation in relationship to hypertension and progressive cystic kidney disease in the ARPKD orthologous polycystic kidney (PCK) rat. Clinical and histological measures of kidney disease, kidney RAS gene expression by quantitative real-time PCR, angiotensin II (Ang II) immunohistochemistry, and systemic Ang I and II levels were assessed in 2-, 4-, and 6-month-old cystic PCK and age-matched normal rats. PCK rats developed hypertension and progressive cystic kidney disease without significant worsening of renal function or relative kidney size. Intrarenal renin, ACE and Ang II expression was increased significantly in cystic kidneys; angiotensinogen and Ang II Type I receptor were unchanged. Systemic Ang I and II levels did not differ. This study demonstrates that intrarenal, but not systemic, RAS activation is a prominent feature of ARPKD. These findings help reconcile previous conflicting reports and suggest that intrarenal renin and ACE gene upregulation may represent a novel mechanism for hypertension development or exacerbation in ARPKD.

Topics: Aging; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Hypertension; Kidney; Male; Mutation; Peptidyl-Dipeptidase A; Polycystic Kidney, Autosomal Recessive; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Time Factors

Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg(-1)) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P=0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage.

Topics: Angiotensin II; Angiotensinogen; Animals; bcl-2-Associated X Protein; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Heart; Heart Failure; Heart Rate; Humans; Hydrazones; Hypertension; Major Histocompatibility Complex; Male; Pyridazines; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan

Genetic and functional data support a role for angiotensinogen in blood pressure control, and many population studies have suggested that polymorphisms in the angiotensinogen gene contribute to hypertension. Two common haplotypes of the human angiotensinogen gene are -6A/235T and -6G/235M. To study their contributions to blood pressure regulation in a controlled model system, we developed triple-transgenic mice expressing either -6A/235T or -6G/235M human angiotensinogen, expressing either an overexpressed and poorly regulated (REN9) or a tightly regulated (PAC160) human renin, and all carrying a null mutation in the endogenous murine angiotensinogen gene. These humanized mice were then examined for blood pressure differences at baseline and after a high-salt diet, changes in cardiovascular organ weight, and differences in angiotensinogen and renin gene expression. Mice expressing the -6G/235M haplotype on the PAC160 background exhibited increased blood pressure and cardiac hypertrophy at baseline. In contrast, all of the mice with the REN9 background had equivalent baseline blood pressures. On the REN9 background, there was a greater increase in blood pressure in -6A/235T in response to a high-salt diet, providing evidence it may be a susceptibility allele. There were no differences in angiotensinogen expression between haplotypes on either background strain. The data suggest that the impact of angiotensinogen haplotypes on cardiovascular end points may be dependent on renin status and environmental influences, such as dietary sodium. These insights may help explain the discrepancies among observational studies that have examined roles for the -6A/235T and -6G/235M angiotensinogen haplotypes in varied human populations.

Topics: Alleles; Angiotensinogen; Animals; Blood Pressure; Genetic Variation; Genotype; Haplotypes; Hypertension; Mice; Mice, Transgenic; Renin; Sodium, Dietary; Telemetry

Meta-analyses of genetic association studies are usually performed using a single polymorphism at a time, even though in many cases the individual studies report results from partially overlapping sets of polymorphisms. We present here a multipoint (or multilocus) method for multivariate meta-analysis of published population-based case-control association studies. The method is derived by extending the general method for multivariate meta-analysis and allows for multivariate modelling of log(odds ratios (OR)) derived from several polymorphisms that are in linkage disequilibrium (LD). The method is presented in a genetic model-free approach, although it can also be used by assuming a genetic model of inheritance beforehand. Furthermore, the method is presented in a unified framework and is easily applied to both discrete outcomes (using the OR), as well as to meta-analyses of a continuous outcome (using the mean difference). The main innovation of the method is the analytical calculation of the within-studies covariances between estimates derived from linked polymorphisms. The only requirement is that of an external estimate for the degree of pairwise LD between the polymorphisms under study, which can be obtained from the same published studies, from the literature or from HapMap. Thus, the method is quite simple and fast, it can be extended to an arbitrary set of polymorphisms and can be fitted in nearly all statistical packages (Stata, R/Splus and SAS). Applications in two already published meta-analyses provide encouraging results concerning the robustness and the usefulness of the method and we expect that it would be widely used in the future.

Topics: Angiotensinogen; Coronary Artery Disease; CX3C Chemokine Receptor 1; Genome-Wide Association Study; Humans; Hypertension; Linkage Disequilibrium; Meta-Analysis as Topic; Models, Genetic; Molecular Epidemiology; Multivariate Analysis; Odds Ratio; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Chemokine

Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups.. The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style).. Although there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype.. The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors.

Topics: Angiotensinogen; Anxiety; Cohort Studies; Female; Genotype; Heart Rate; Humans; Hypertension; Life Style; Male; Sex Factors

Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at -6, and the -6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with -6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with -6G. We have found that the hAGT gene has three additional SNPs (A/G at -1670, C/G at -1562, and T/G at -1561). Variants -1670A, -1562C, and -1561T almost always occur with -6A, and variants -1670G, -1562G, and -1561G almost always occur with -6G. Therefore, the hAGT gene may be subdivided into either -6A or -6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with -6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with -6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the -6A or -6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing -6A haplotype. Our studies also show that transgenic mice containing -6A haplotype have increased plasma AGT level and increased blood pressure as compared with -6G haplotype. Our studies explain the molecular mechanism involved in association of the -6A allele of the hAGT gene with hypertension.

Topics: Alleles; Angiotensinogen; Animals; Blood Pressure; Haplotypes; Hepatocyte Nuclear Factor 1-alpha; Humans; Hypertension; Liver; Mice; Mice, Transgenic; Polymorphism, Single Nucleotide; Receptors, Glucocorticoid; Renin

We evaluated the prevalences of ACE/ID, AGT/M235T, AT1R/A1166C, and CYP11B2/C344T genetic polymorphisms and their association with left ventricular hypertrophy (LVH) in Uzbek hypertensive men.. The study included 172 Uzbek men (mean age 47±10 years) with untreated essential hypertension (EH) of grade 1-2 and 60 normotensive subjects (mean age 41±10 years). All subjects underwent complete M-mode echocardiography to determine left ventricular mass (LVM) and LVM index (LVMI). Genomic DNA was extracted from peripheral blood and was analyzed using polymerase chain reaction-restriction fragment length polymorphism assays.. Left ventricular hypertrophy was detected in 148 hypertensive patients (86.1%). The frequencies of the D-allele of the ACE gene and T-allele of the CYP11B2 gene were higher among hypertensive patients than in the controls. There was a significant association between the AGT/M235T polymorphism and LVH. The 235T-allele of the AGT gene, the D-allele of the ACE gene, and the 344T-allele of the CYP11B2 gene were identified as "damaging" alleles. All the patients had "damaging" alleles, the number being one in only seven patients (4.1%), two in 52 patients (30.2%), and three in 89 patients (51.7%). The severity of LVH significantly increased with the number of "damaging" alleles. Among paired carriage of "damaging" alleles, the combination of the D+235T-alleles was found as the most unfavorable pair associated with the degree of LVH.. There is an association between EH and ACE/ID and CYP11B2/C344T gene polymorphisms in Uzbek males, with higher frequencies of the D-allele of the ACE gene and T-allele of the CYP11B2 gene. Our findings provide evidence for the association of AGT/M235T polymorphism with LVH in Uzbek males, combination of the D+235T-alleles being the most unfavorable pair associated with LVH.

Topics: Adult; Angiotensinogen; Case-Control Studies; Cytochrome P-450 CYP11B2; Echocardiography; Gene Frequency; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prevalence; Receptor, Angiotensin, Type 1; Uzbekistan

There is increasing evidence suggesting the importance of evaluating gene-environment interactions in the genetic study of coronary artery disease (CAD). We investigated the association of multiple single nucleotide polymorphisms in the angiotensinogen (AGT) gene with CAD, considering the interaction between the genetic and non-genetic factors, using a larger and ethnically homogeneous angiographic cohort. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with CAD and 519 without) were recruited. T174M (rs4762), M235T (rs699), G-6A, A-20C, G-152A, and G-217A polymorphisms of the AGT gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects defined by the multilocus data and detection of gene-environment interaction by incorporating interaction terms in the model. We found significant differences in global AGT gene haplotype profile between patients with and without CAD (the global score statistic=25.411, P=0.008). Significant interactions between AGT gene haplotypes, gender and hypertension were detected. We also used haplotype counting to directly estimate the odds ratio of each AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups defined by gender and hypertension, providing strong evidence of gene-environment interaction. Female gender synergistically enhances (or male gender reverses) the effects of AGT gene haplotypes on the risk of CAD in the presence of hypertension. In conclusion, the effect of AGT gene haplotypes on the risk of CAD was significantly increased in women with hypertension, which highlights the importance of evaluating gene-environment interactions in the genetic study of CAD.

Topics: Angiography; Angiotensinogen; Cardiac Catheterization; Cohort Studies; Coronary Artery Disease; Female; Haplotypes; Humans; Hypertension; Male; Models, Genetic; Polymorphism, Genetic; Regression Analysis; Risk; Sex Factors

Renin-angiotensin (RAS) genes, a group of promising candidate genes involved in essential hypertension (EH), play a key role in blood pressure regulation. Recently, a series of novel RAS gene polymorphisms were reported, which significantly influence the rate of the gene transcription. This study was designed to explore the association between the RAS gene polymorphisms and EH in a remote countryside population. We examined six polymorphisms in the main component genes of RAS: angiotensin-converting enzyme (ACE) (I/D), angiotensinogen (AGT) (A-6G, A-20C, G-217A and T174 M) and angiotensin type 1 receptor (AT1R) (A1166C). Six polymorphisms were genotyped by gene chip technology. Association studies were performed in 220 EH patients and 235 normotensives. Our results revealed that AGT A-6G, T174 M and ACE-I/D were significantly associated with EH (AGT A-6G: AG+GG vs AA; OR=1.36; 95% CI=1.04-1.77. T174M: CT+TT vs CC; OR=1.45; 95% CI=1.15-1.90. ACE I/D: ID+DD vs II; OR=1.171; 95% CI=1.00-1.37). Moreover the logistic regression analysis suggested that the haplotype of AGT -6A, 174C, -217G and -20A might decrease the risk of EH (OR=0.64; 95% CI=0.49-0.83), after adjusting the confounding factors of gender, age and BMI. In conclusion, the AGT A-6G, T174 M and ACE I/D polymorphisms are associated with EH and the AGT haplotype -6A, 174C, -217G and -20A decrease the risk of EH in the southern Chinese population.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Asian People; Blood Pressure; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Logistic Models; Male; Middle Aged; Odds Ratio; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Single Nucleotide; Population Surveillance; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Assessment

Hypertension and osteoporosis are two major age-related disorders; however, the underlying molecular mechanism for this comorbidity is not known. The renin-angiotensin system (RAS) plays a central role in the control of blood pressure and has been an important target of antihypertensive drugs. Using a chimeric RAS model of transgenic THM (Tsukuba hypertensive mouse) expressing both the human renin and human angiotensinogen genes, we showed in this study that activation of RAS induces high turnover osteoporosis with accelerated bone resorption. Transgenic mice that express only the human renin gene were normotensive and yet exhibited a low bone mass, suggesting that osteoporosis occurs independently of the development of hypertension per se. Ex vivo cultures showed that angiotensin II (AngII) acted on osteoblasts and not directly on osteoclast precursor cells and increased osteoclastogenesis-supporting cytokines, RANKL and vascular endothelial growth factor (VEGF), thereby stimulating the formation of osteoclasts. Knockdown of AT2 receptor inhibited the AngII activity, whereas silencing of the AT1 receptor paradoxically enhanced it, suggesting a functional interaction between the two AngII receptors on the osteoblastic cell surface. Finally, treatment of THM mice with an ACE inhibitor, enalapril, improved osteoporosis and hypertension, whereas treatment with losartan, an angiotensin receptor blockers specific for AT1, resulted in exacerbation of the low bone mass phenotype. Thus, blocking the synthesis of AngII may be an effective treatment of osteoporosis and hypertension, especially for those afflicted with both conditions.

Topics: Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Bone Remodeling; Humans; Hypertension; Mice; Osteoblasts; Osteoporosis; RANK Ligand; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Vascular Endothelial Growth Factor A

Increased angiotensinogen (AGT) production by white adipose tissue has been related to not only obesity but also hypertension. Several studies have highlighted the importance of the angiotensin II type 2 receptor (AT2) in the regulation of blood pressure and fat mass, but the relevance of this transporter in a physiopathological model of increased AGT production, as it occurs in obesity, has not yet been investigated. We used transgenic mice that display either a deletion of AT2 (AT2 KO), an overexpression of AGT (OVEX), or both compound mutants (KOVEX). Results demonstrated that adipocyte hypertrophy and increased lipogenic gene expression induced by adipose AGT overproduction was rescued by deletion of AT2. In line with AGT overexpression, KOVEX and OVEX mice have similar increased plasma AGT levels. However, KOVEX mice display a higher blood pressure than OVEX mice. In kidney, renin expression was clearly reduced in OVEX mice, and its expression was normalized in KOVEX mice. Taken together, we demonstrated that the loss of AT2 expression was sufficient to rescue obesity induced by adipose tissue AGT overexpression and confirmed the necessary role of AT2 for the onset of obesity in this model. Furthermore, despite a reduction of adipose mass in KOVEX, AT2 deficiency caused increased renin production, further worsening the hypertension caused by AGT overexpression.

Topics: Adipose Tissue; Adiposity; Angiotensinogen; Animals; Body Weight; Cell Count; Cells, Cultured; Female; Genotype; Hypertension; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Receptor, Angiotensin, Type 2

The aim of the present study was to determine the impact of increased consumption of phytosterols or phytostanols on blood pressure and renal blood pressure regulatory gene expression in stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar-Kyoto (WKY) inbred rats. SHRSP and WKY inbred rats (10/group) were fed a control diet or a diet supplemented with phytosterols or phytostanols (2.0 g/kg diet). After 5 weeks, SHRSP rats demonstrated higher systolic and diastolic blood pressures than WKY inbred rats. SHRSP rats that consumed the phytosterol or phytostanol supplemental diets displayed a 2- or 3-fold respective increase in the diastolic blood pressure than those that consumed the control diet. Angiotensinogen (Agt), angiotensin I-converting enzyme 1 (Ace1), nitric oxide synthase (Nos) 1, Nos3, cyclooxygenase 2 (Cox2) and THUMP domain containing 1 were expressed at higher levels in SHRSP compared with WKY inbred rats. Renin and angiotensin II receptor type 1a were expressed at lower levels in SHRSP than WKY inbred rats. Phytostanol supplementation up-regulated the expression of Ace1 and Nos3 in SHRSP rats. Phytosterol supplementation increased the mRNA levels of Nos1 and spondin 1 (Spon1) in SHRSP and WKY inbred rats. Cox2 mRNA levels were elevated in both phytosterol- and phytostanol-supplemented SHRSP and WKY inbred rats. Therefore, the increased blood pressure in SHRSP rats may be partly due to altered renal expression of blood pressure regulatory genes. Specifically, up-regulation of Ace1, Nos1, Nos3, Cox2 and Spon1 were associated with the increased diastolic blood pressure observed in phytosterol- or phytostanol-supplemented SHRSP rats.

Topics: Angiotensinogen; Animals; Blood Pressure; Cyclooxygenase 2; Diastole; Gene Expression; Gene Expression Regulation; Hypertension; Kidney; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Phytosterols; Phytotherapy; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

We reported previously that urinary angiotensinogen (UAGT) levels provide a specific index of the intrarenal renin-angiotensin system (RAS) status in angiotensin II-dependent hypertensive rats. To study this system in humans, we recently developed a human angiotensinogen ELISA. To test the hypothesis that UAGT is increased in hypertensive patients, we recruited 110 adults. Four subjects with estimated glomerular filtration levels <30 mL/min per 1.73 m(2) were excluded because previous studies have already shown that UAGT is highly correlated with estimated glomerular filtration in this stage of chronic kidney disease. Consequently, 106 paired samples of urine and plasma were analyzed from 70 hypertensive patients (39 treated with RAS blockers [angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers; systolic blood pressure: 139+/-3 mm Hg] and 31 not treated with RAS blockers [systolic blood pressure: 151+/-4 mm Hg]) and 36 normotensive subjects (systolic blood pressure: 122+/-2 mm Hg). UAGT, normalized by urinary concentrations of creatinine, were not correlated with race, gender, age, height, body weight, body mass index, fractional excretion of sodium, plasma angiotensinogen levels, or estimated glomerular filtration. However, UAGT/urinary concentration of creatinine was significantly positively correlated with systolic blood pressure, diastolic blood pressure, urinary albumin:creatinine ratio (r=0.5994), and urinary protein:creatinine ratio (r=0.4597). UAGT/urinary concentration of creatinine was significantly greater in hypertensive patients not treated with RAS blockers (25.00+/-4.96 microg/g) compared with normotensive subjects (13.70+/-2.33 microg/g). Importantly, patients treated with RAS blockers exhibited a marked attenuation of this augmentation (13.26+/-2.60 microg/g). These data indicate that UAGT is increased in hypertensive patients, and treatment with RAS blockers suppresses UAGT, suggesting that the efficacy of RAS blockade to reduce the intrarenal RAS activity can be assessed by measurements of UAGT.

Topics: Angiotensinogen; Biomarkers; Blood Pressure; Case-Control Studies; Creatinine; Enzyme-Linked Immunosorbent Assay; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Regression Analysis; Renin-Angiotensin System

The renin-angiotensin system plays an important role in the etiology of cardiovascular diseases. Three transgenic mouse lines overexpressing rat angiotensinogen (rAOGEN) were generated. The aim of our study was to characterize the originally undescribed second transgenic line TGM(rAOGEN)102. The transgene tissue distribution and expression of brain natriuretic peptide and collagen type III were investigated by ribonuclease protection assay. Catheter measurements of blood pressure and cardiac function were performed in anesthetized mice. End-organ fibrosis was further assessed by van Gieson staining. In line TGM(rAOGEN)102, the rAOGEN transgene was mainly expressed in liver and brain but could also be detected in hearts, kidneys, and lungs. Transgenic mice developed excessive chronic hypertension compared with their wild-type littermates. The rise of blood pressure was paralleled by cardiac hypertrophy, impaired cardiac function, and increased expression of brain natriuretic peptide. Pronounced fibrosis was detected in the hearts, lungs, and kidneys of transgenic mice. Our data indicate that overexpression of rAOGEN in mice leads to excessive hypertension, cardiac hypertrophy, impaired heart function, and pronounced fibrosis. Thus, this line TGM(rAOGEN)102 provides a new model to study hypertension-mediated end-organ damage and to evaluate new antihypertensive or cardioprotective drugs.

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Fibrosis; Genes; Heart; Hypertension; Kidney; Male; Mice; Mice, Transgenic; Rats; Rats, Transgenic; Renin-Angiotensin System

Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system.

Topics: Albuminuria; Angiotensinogen; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Drug Implants; Estradiol; Female; Hypertension; Kidney; Male; Orchiectomy; Ovariectomy; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Sex Factors; Sodium Chloride, Dietary; Telemetry; Testosterone; Time Factors; Up-Regulation

The renin-angiotensin aldosterone system (RAAS) plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT), MboI of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin) of RAAS genes in Malaysian essential hypertensive and type 2 diabetic subjects.. RAAS gene polymorphisms were determined using mutagenically separated PCR and PCR-RFLP method in a total of 270 subjects consisting of 70 hypertensive subjects without type 2 diabetes mellitus (T2DM), 60 T2DM, 65 hypertensive subjects with T2DM and 75 control subjects.. There was significant difference found in age, body mass index, systolic/diastolic blood pressure, fasting plasma glucose and high density lipoprotein cholesterol levels between the hypertensive subjects with or without T2DM and control subjects. No statistically significant differences between groups were found in the allele frequency and genotype distribution for A20C variant of AGT gene, MboI of renin, Gly460Trp of aldosterone and Lys173Arg of adducin (p > 0.05). However, the results for A6G of AGT gene revealed significant differences in allele and genotype frequencies in essential hypertension with or without T2DM (p < 0.001).. Among the five polymorphisms of RAAS genes only A6G variant of AGT gene was significantly associated in Malaysian essential hypertensive and type 2 diabetic subjects. Therefore, A6G polymorphism of the AGT gene could be a potential genetic marker for increased susceptibility to essential hypertension with or without T2DMin Malaysian subjects.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Cytochrome P-450 CYP11B2; Diabetes Mellitus, Type 2; Female; Genetic Markers; Genetic Predisposition to Disease; Humans; Hypertension; Malaysia; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System

Kidney androgen-regulated protein (KAP), a proximal tubule androgen-regulated gene, codes for a protein of unknown function.. To investigate the consequences of KAP overexpression in kidney, we produced KAP transgenic mice and performed microarray expression analyses in kidneys of control and transgenic males. Downregulation of the androgen-sensitive Cyp4A14 monooxygenase gene in KAP transgenic mice prompted us to analyze blood pressure levels, and we observed that transgenic mice were hypertensive. Inhibition of 20-hydroxyeicosatetraenoic acid synthesis by N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) reduced the increased 20-hydroxyeicosatetraenoic acid levels in urine and normalized arterial pressure in transgenic mice, as did the NADPH oxidase inhibitor apocynin. Increased oxidative stress in transgenic mice was demonstrated by (1) enhanced excretion of urinary markers of oxidative stress, 8-iso-prostaglandin F2alpha, 8-hydroxydeoxyguanosine, and thiobarbituric acid-reacting substances; (2) augmented mitochondrial DNA damage and malondialdehyde levels in kidneys; and (3) diminished catalase and glutathione peroxidase activity in transgenic kidneys. Mice exhibited renal defects that included focal segmental glomerulosclerosis, proteinuria, glycosuria, and fibrosis.. Taken together, these results indicate that KAP expression is critical for cardiovascular-renal homeostasis maintenance and that hypertension is associated with increased oxidative stress. This is the first report showing that overexpression of an androgen-regulated, proximal tubule-specific gene induces hypertension. These observations may shed light on the molecular pathophysiology of gender differences in the prevalence and severity of hypertension and chronic renal disease.

Topics: Angiotensinogen; Animals; Blood Pressure; Catalase; DNA Damage; Exons; Gene Expression Regulation; Glutathione Peroxidase; Hemodynamics; Humans; Hypertension; Immunohistochemistry; Kidney; Kidney Diseases; Male; Mice; Mice, Transgenic; Microscopy, Confocal; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Polymerase Chain Reaction; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA; Superoxide Dismutase

We investigated the associations between hypertension status and the genotypes of four single nucleotide polymorphism (SNP) sites in four hypertension-related genes (Angiotensinogen [AGT], Angiotensin I Converting Enzyme [ACE], Angiotensinogen II receptor, subtype 1 [AGTR1], and Alpha 1-Antichymotrypsin [ACT or SERPINA3]), in an African American sample.. DNA from 628 participants of the Carolina African American Twin Study of Aging project, a population-based study of African American adult twins, was genotyped using SNPs shown to be associated with hypertension in other studies.. The ACE SNP (ACE4 or A-240T) was associated with hypertension (P = .047 in a generalized estimating equations alternating logistics regression model that included age, body mass index, sex, and education. The analysis indicated a protective effect of the TT genotype (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.03-2.48, P = .04) and of the AT genotype (OR 1.91, 95% CI 1.01-3.62, P = .047) compared with the AA genotype.. These results extend previous findings of associations of various polymorphisms of ACE to hypertension and support the association of hypertension to the A allele of ACE4. The potential for this polymorphism to alter expression by its position in the gene's promoter region suggests that future studies of altered ACE protein activity are warranted.

Topics: Adult; alpha 1-Antichymotrypsin; Angiotensinogen; Black or African American; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Twins

A case-control study of 538 individuals investigated whether the angiotensinogen gene (AGT) might be implicated in the pathogenesis of essential hypertension in the Hani and Yi populations of China. Genotypes for two diallelic DNA polymorphisms observed at amino acid residues 174 (T174M) and 235 (M235T) within the coding sequence were determined. M235T and T174M genotyping with PCR-RFLP was performed in 267 normotensive subjects and 271 hypertensive subjects. No significant difference was found between normotensives and hypertensives in genotype distribution and allele frequency for either M235T or T174M in the Hani or the Yi populations (P > 0.05). Relative to carriers of the 235T/235T and 174T/174T combination, the others had a significantly elevated risk of hypertension (OR = 1.62, 95% CI 1.02-2.59; P = 0.043) in the Hani population. The AGT M235T and T174M variants in combination may play a role in the genetic predisposition to develop essential hypertension in the Hani minority of China.

Topics: Adult; Aged; Alleles; Amino Acid Substitution; Analysis of Variance; Angiotensinogen; Blood Pressure; Case-Control Studies; Chi-Square Distribution; China; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Hypertension; Linkage Disequilibrium; Logistic Models; Male; Middle Aged; Polymorphism, Genetic

Angiotensin-(1-12) [ANG-(1-12)] is a newly identified peptide detected in a variety of rat tissues, including the brain. To determine whether brain ANG-(1-12) participates in blood pressure regulation, we treated male adult (mRen2)27 hypertensive rats (24-28 wk of age) with Anti-ANG-(1-12) IgG or Preimmune IgG via an intracerebroventricular cannula for 14 days. Immunoneutralization of brain ANG-(1-12) lowered systolic blood pressure (-43 +/- 8 mmHg on day 3 and -26 +/- 7 mmHg on day 10 from baseline, P < 0.05). Water intake was lower on intracereroventricular day 6 in the Anti-ANG-(1-12) IgG group, accompanied by higher plasma osmolality on day 13, but there were no differences in urine volume, food intake, or body weight during the 2-wk treatment. In Preimmune IgG-treated animals, there were no significant changes in these variables over the 2-wk period. The antihypertensive effects produced by endogenous neutralization of brain ANG-(1-12) suggest that ANG-(1-12) is functionally active in brain pathways regulating blood pressure.

Topics: Angiotensinogen; Angiotensins; Animals; Blood Pressure; Body Weight; Brain; Disease Models, Animal; Drinking; Eating; Hypertension; Immunoglobulin G; Infusion Pumps, Implantable; Male; Osmolar Concentration; Peptide Fragments; Rats; Rats, Transgenic; Renin; Time Factors; Urodynamics

We tested the hypothesis that maternal protein deprivation during gestation results in changes in expression of the systemic renin-angiotensin system in fetal mice. Fetal weight was decreased significantly as a consequence of 50% maternal protein deprivation during second half of gestation. In fetal liver, angiotensinogen protein expression was reduced significantly despite a significant increase in messenger RNA (mRNA). In fetal kidneys, both mRNA and protein levels of renin were increased significantly. In the lungs, we observed a decrease in both angiotensin-converting enzyme I and II mRNA expression, whereas protein expression of both isoforms was increased significantly. The fetal heart showed significant increases in expression of angiotensin II type 1 (AT-1) and type 2 (AT-2) receptors mRNA. Protein expression of AT-1 receptors increased, while that of AT-2 receptors decreased. We conclude that maternal low-protein diet during gestation leads to significant changes in expression of the systemic renin-angiotensin system in fetal mice and may be important in the genesis of hypertension in the adult.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Dietary Proteins; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Hypertension; Mice; Peptidyl-Dipeptidase A; Pregnancy; Pregnancy Complications; Protein-Energy Malnutrition; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; RNA, Messenger

Topics: Angiotensinogen; Binding Sites; Female; Glomerular Mesangium; Humans; Hypertension; Male; Prorenin Receptor; Receptors, Cell Surface; Renin-Angiotensin System; Sensitivity and Specificity; Signal Transduction; Vacuolar Proton-Translocating ATPases

1. Hypertensive mice expressing the human renin (REN) and angiotensinogen (AGT) genes are used as a model for human hypertension. 2. The aim of the present study was to investigate the cellular expression and distribution of inducible nitric oxide synthase (iNOS) using immunohistochemistry in lung, heart and kidney tissues from a model of human hypertension using male and female double-transgenic (h-Ang 204/1h-Ren6) mice and wild-type C57/BI6J mice as controls. 3. In the kidney, the pattern of iNOS expression in various renal microanatomical regions during hypertension was similar to that of age-matched controls, except in the medullary ascending limb (MAL). In hypertension, iNOS expression was downregulated in the MAL. No significant differences in iNOS expression were seen between control or hypertensive mice in various cardiac microanatomical locations. In the lungs of hypertensive mice, iNOS expression was upregulated in bronchial airway epithelium and bronchial and vascular smooth muscle cells, but downregulated in alveolar macrophages, alveolar septa and pulmonary vascular endothelial cells. Expression of iNOS was similar between male and female mice in the kidney, heart and lungs. 4. In conclusion, iNOS regulation in hypertension is complex and depends on the cell type in which it is expressed and the localization of the cell type in the cardiorenal and pulmonary systems.

Topics: Angiotensinogen; Animals; Cells, Cultured; Female; Gene Expression Regulation, Enzymologic; Humans; Hypertension; Kidney; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Myocardium; Myocytes, Smooth Muscle; Nitric Oxide Synthase Type II; Renin

Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Chronic Disease; Disease Models, Animal; Heart Diseases; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Macrophages; Male; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Transforming Growth Factor beta; Ventricular Remodeling

To examine the contribution of six cardiovascular polymorphisms to the occurrence of a first event of ischemic heart disease (IHD) in a primary care population with a high prevalence of hypertension. Furthermore, we specified the data for sex and age.. In this cross sectional case-control study, patients with a first event of IHD (157) and event-free controls (571) were studied. Both the groups were genotyped for the angiotensin II type 1 receptor (A1166C), angiotensinogen (M235 T), angiotensin converting enzyme (4656rpt), endothelial nitric oxide synthase (E298D), G-protein beta3 subunit (C825 T), and alpha-adducin (G460W) polymorphisms. Univariate and multivariate odds ratios (ORs) were calculated to assess the association between a first ischemic event and these polymorphisms. Sliding mean analyses were performed to show age-specific associations.. Multivariate ORs indicated a protective association for the carrier status of the T-allele of AGT, overall [OR = 0.69 (0.34-0.90)] and for males [OR = 0.58 (0.27-0.89)]. Sliding mean analyses showed a continuous protective association with IHD of the T-allele of AGT with increasing age in males, whereas in females an increased risk for IHD was observed with a maximum OR of 1.6 at the age of 56 years.. In this population the T-allele of the AGT polymorphism is protective for a first event of IHD in males.

Topics: Age Factors; Aged; Angiotensinogen; Calmodulin-Binding Proteins; Case-Control Studies; Cross-Sectional Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Logistic Models; Male; Middle Aged; Myocardial Ischemia; Nitric Oxide Synthase Type III; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Primary Health Care; Receptor, Angiotensin, Type 1; Risk Assessment; Risk Factors; Sex Factors

The renin-angiotensin system (RAS) has an important role in cardiovascular homeostasis. This study determined the influence of water deprivation during pregnancy on the development of the RAS in rats, and examined blood pressure (BP) in the adolescent offspring. Pregnant rats were water deprived for 3 days at late gestation, and we examined fetal cardiac ultrastructure, as well as heart angiotensin (Ang) II receptor protein and mRNA, liver angiotensinogen and plasma Ang II concentrations. We also tested cardiovascular responses to i.v. Ang II in the young offspring. In utero exposure to maternal water deprivation significantly decreased fetal body and heart weight, and increased fetal plasma sodium and osmolality. Fetal liver angiotensinogen mRNA, plasma Ang I and Ang II concentrations were also increased. Although fetal AT(1a) and AT(1b) receptor mRNA and AT(1) protein were not changed, AT(2) receptor mRNA and protein levels in the heart were significantly increased following maternal dehydration. Prenatal exposure to maternal water deprivation had no effect on baseline BP; however, it significantly increased BP in response to i.v. Ang II infusion, and decreased baroreflex sensitivity in the offspring. In addition, the heart AT(2) receptor mRNA and protein were higher in the offspring exposed to prenatal dehydration. The results of this study demonstrate that prenatal dehydration affected the RAS development associated with an Ang II-increased BP in fetal origin.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Baroreflex; Birth Weight; Blood Pressure; Female; Fetal Development; Gene Expression; Heart; Heart Rate; Hypertension; Liver; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; RNA, Messenger; Water Deprivation

This study is to establish a diabetic-hypertensive model in rats. After the induction of diabetes by streptozocin (STZ), rats were maintained with free access to rat chow and 1% NaCl drinking water. Blood pressure was monitored at conscious state by tail-cuff weekly till it was 50 mmHg higher than normal animal steadily. Finally, blood pressure was measured by catheterization of the right carotid artery and plasma ET-1 and Ang II, kidney Ang II and angiotensinogen or preproendothelin gene expression in liver or aorta were assayed separately. STZ-diabetic rats that maintained with 1% NaCl drinking water exhibited obviously increasing blood pressure since the third week. Then the pressure reached 150 mmHg at the 6th week and was maintained until the 11th week. Till the 12th week, the blood pressure reached to higher than 160 mmHg. In addition, these high blood pressure rats were accompanied with increased blood plasma ET-1 and Ang II and augmented gene expression levels of angiotensinogen in kidneys and preproendothelin in aorta tissues. Loading sodium chloride chronically to STZ-diabetic rats could prepare a diabetic-hypertensive rat model.

Topics: Angiotensin II; Angiotensinogen; Animals; Aorta; Blood Pressure Determination; Diabetes Mellitus, Experimental; Endothelin-1; Hypertension; Kidney; Male; Rats; Rats, Wistar

Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy-related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease.

Topics: Angiotensinogen; Animals; Animals, Newborn; Blood Pressure; Cardiomegaly; Chronic Disease; Disease Models, Animal; Female; Humans; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Renin; Renin-Angiotensin System

In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determine the interaction of age and genotype on this intermediate phenotype.. Three hundred fifteen participants had renal plasma flow response to subpressor doses of angiotensin II (3 ng/kg/min) measured by para-aminohippuric acid clearance in high-sodium balance. Individuals were divided by median age into young (<45 years) and older (> or =45 years) sets. A subset of participants was also studied after administration of captopril.. Age, baseline renal plasma flow, BMI and angiotensinogen 235 genotype independently predicted renal plasma flow responsiveness to angiotensin II. Renal plasma flow responses were lower in older individuals than younger (P = 0.03, hypertensive patients; P = 0.004, normotensive individuals). Both hypertensive patients and normotensive individuals carrying either angiotensinogen 235MM or MT genotypes showed this inverse association (P = 0.005, hypertensive patients; P = 0.05, normotensive individuals). However, among angiotensinogen 235TT homozygotes the pattern differed: normotensive individuals had a fall in renal vascular responsiveness with age (P = 0.01) but hypertensive patients did not (P = 0.72). Young hypertensive patients already showed blunted responses. Of all genotype subsets, only angiotensinogen 235TT hypertensive patients showed enhancement (P = 0.03) of the renal vascular responsiveness to angiotensin II after captopril.. The angiotensinogen 235TT variant predicts premature blunting of renal vascular responsiveness among young hypertensive patients. This abnormal response is corrected by angiotensin-converting enzyme inhibition. This first report of age and genotype interaction may have important implications in the profiling and management of essential hypertension.

Topics: Adult; Age Factors; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Female; Genotype; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Renal Circulation; Renin-Angiotensin System; Vasoconstrictor Agents

The aim of this study was to assess whether the association between angiotensin-converting enzyme (ACE) inhibitor use and the incidence of treated diabetes mellitus is modified by genetic polymorphisms in the renin-angiotensin system (RAS).In a nested case-control study, treated hypertensive patients were genotyped for ACE (insertion (I)/deletion (D)), angiotensinogen (AGT; M235T) and angiotensin II type 1 receptor (AGTR1; A1166C). Cases of newly treated diabetes were identified based on pharmacy records and controls were not yet drug treated for diabetes (case:control ratio 1:10). Self-administered questionnaires and physical examinations were used to assess risk factors for diabetes mellitus. Logistic regression was used to calculate the relative risk of diabetes associated with ACE inhibitor use relative to other antihypertensive treatment, stratified by the RAS genotypes. Among 205 cases and 2050 controls, homozygous 1166A carriers of the AGTR1 gene had a significantly decreased incidence of diabetes associated with current use of ACE inhibitors (odds ratio, OR: 0.47; 95% CI: 0.26-0.84), whereas this incidence was increased among 1166C allele carriers (OR: 1.32; 95% CI: 0.81-2.14). The interaction OR was 3.21 (95% CI: 1.53-6.75). ACE I allele carriers had a significantly reduced incidence of diabetes associated with ACE inhibitors use (OR: 0.63; 95% CI: 0.41-0.98), whereas DD homozygotes had no reduced risk (OR: 0.95; 95% CI: 0.46-1.96). The risk of diabetes associated with ACE inhibitor use was not significantly modified by the AGT-M235T polymorphism. Treatment with ACE inhibitors in hypertensive subjects significantly reduces the occurrence of diabetes in homozygous 1166A carriers of the AGTR1 gene and carriers of the ACE I allele, but not in 1166C allele carriers of the AGTR1 gene and in homozygous ACE D allele carriers.

Topics: Alleles; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Diabetes Mellitus; DNA; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Hypertension; Incidence; Linkage Disequilibrium; Male; Middle Aged; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Retrospective Studies

The objectives of this study were to determine the effects of chronic angiotensin II (ANG II) infusions on ANG II content and angiotensinogen expression in the mouse kidney and the role of the angiotensin II type 1 receptor (AT(1)R) in mediating these changes. C57BL/6J male mice were subjected to ANG II infusions at doses of 400 or 1,000 ng.kg(-1).min(-1) either alone or with an AT(1)R blocker (olmesartan; 3 mg.kg(-1).day(-1)) for 12 days. Systolic and mean arterial pressures were determined by tail-cuff plethysmography and radiotelemetry. On day 13, blood and kidneys were collected for ANG II determinations by radioimmunoanalysis and intrarenal angiotensinogen expression studies by quantitative RT-PCR, Western blotting, and immunohistochemistry. ANG II infusions at the low dose elicited progressive increases in systolic blood pressure (135 +/- 2.5 mmHg). In contrast, the high dose induced a rapid increase (152 +/- 2.5, P < 0.05 vs. controls, 109 +/- 2.8). Renal ANG II content was increased by ANG II infusions at the low dose (1,203 +/- 253 fmol/g) and the high dose (1,258 +/- 173) vs. controls (499 +/- 40, P < 0.05). Kidney angiotensinogen mRNA and protein were increased only by the low dose to 1.13 +/- 0.02 and 1.26 +/- 0.10, respectively, over controls (1.00, P < 0.05). These effects were not observed in mice infused at the high dose and those receiving olmesartan. The results indicate that chronic ANG II infusions augment mouse intrarenal ANG II content with AT(1)R-dependent uptake occurring at both doses, but only the low dose of infusion, which elicited a slow progressive response, causes an AT(1)R-dependent increase in intrarenal angiotensinogen expression.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Organ Size; Receptor, Angiotensin, Type 1; Renin

Genetic variation in the human angiotensinogen gene (AGT) influences plasma AGT concentration and susceptibility to essential hypertension by a mechanism that remains to be clarified. When one or two additional copies of the gene were inserted by gene titration (by homologous recombination with gap-repair at the AGT locus), both plasma AGT and arterial pressure were elevated in the physiological range in the mouse. The causal dependency between plasma AGT and blood pressure and the relative contribution of the various tissues that express AGT to these two phenotypic parameters remained to be determined. To address these issues, we generated a transgenic mouse with overexpression of the mouse AGT gene restricted to the liver. The transgene was examined in two contrasted genetic backgrounds, the sodium-sensitive C57BL/6J and the sodium-resistant A/J. Transgenic and control male animals underwent continuous cardiovascular monitoring by telemetry for 14 days while under a standard sodium diet (0.2%). Moderate but significant increases in plasma AGT (40%, p = 0.01) and systolic blood pressure (4-6 mmHg, p ranging from 0.01 to <0.001) were observed in the sodium-sensitive background, but not in the sodium-resistant animals. Statistical analysis of a large number of consecutive, repeated measurements of blood pressure afforded power to detect small effects in the physiological range by use of advanced mixed models of analysis of variances and covariances. Although plasma renin activity was increased in the sodium-sensitive background, it did not reach statistical significance. These observations underline a potential contribution of systemic AGT to the mechanism of AGT-mediated hypertension, but the significance of sodium sensitivity in the genetic background suggests participation of the kidney in expression of the elevated blood pressure phenotype, a matter that will warrant further studies. They also highlight the challenge of identifying the contribution of individual genes in complex inheritance, as their effects are modulated by other genetic and environmental determinants.

Topics: Aldosterone; Angiotensinogen; Animals; Gene Dosage; Genetic Engineering; Hypertension; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organ Specificity; Renin-Angiotensin System; Transgenes

Topics: Angiotensinogen; Cross-Sectional Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Life Style; Polymorphism, Genetic; Sodium Chloride, Dietary; Weight Loss

Almost 50% of hypertensive individuals manifest blood pressure changes in response to salt depletion or repletion and are termed "salt sensitive" (SS). Blunted activity of the endothelin (ET) system and the renin-angiotensin-aldosterone system (RAAS) have been reported as possible mechanisms contributing to salt sensitivity. Data are available that endothelin receptor subtype B (ETBR)-deficient rats develop salt-sensitive hypertension when fed a high-salt diet. Whether the ETBR gene (EDNRB) is involved in genetic predisposition to human salt-sensitive hypertension has not been studied so far. We screened EDNRB in 104 hypertensive patients (49 salt sensitive and 55 salt resistant) and 110 normotensive controls. No new sequence variation was found, but genotype distribution of the common polymorphism G1065A revealed that the AA + GA genotypes were significantly more frequent in salt-resistant than in salt-sensitive individuals (p = 0.007), suggesting a protective role for the A allele. We also screened angiotensinogen gene AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism ACE I/D and found an association between TT genotype and hypertension. A possible synergistic effect to salt-sensitive hypertension was found by combining EDNRB GG with ACE DD/ID genotypes. In conclusion, our data confirm the role of ET system and RAAS in salt-sensitive hypertension.

Topics: Alleles; Angiotensinogen; DNA Primers; Exons; Genotype; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Chloride

The aim of this study was to determine whether specific single nucleotide polymorphisms (SNPs) and their reconstructed haplotypes in renin-angiotensin-aldosterone system (RAAS) genes were associated with antihypertensive reduction to irbesartan treatment. Thousand one forty-two hypertensives were recruited and received 150 mg irbesartan daily for 4 weeks. Blood pressures (BPs) and blood samples, at postdose on the 28th day, were measured. Predose BPs and plasma irbesartan concentrations were also measured. Involved SNPs in RAAS pathway genes were genotyped. Genotype (-344 TC) in the CYP11B2 had a significantly greater systolic blood pressure (SBP) reduction versus the TT genotype (p = 0.001). Subjects with the 174MM genotype of the angiotensinogen (AGT) gene had a significantly greater average SBP reduction (p = 0.025). The C-344T and T1016C polymorphisms in the CYP11B2 gene were both significantly associated with diastolic blood pressure (DBP) reduction (p = 0.026 or p = 0.003). Overall, the three loci-constructed haplotypes of the CYP11B2 gene were associated with DBP reduction (p = 0.008). Haplo-GLM analyses demonstrated that subjects with haplotype CTA had a significantly greater SBP and DBP reductions (p < 0.001 or p = 0.020), whereas subjects with haplotype TAA had a significantly lower SBP and DBP reductions (p < 0.001). Our findings suggested that SNPs and their reconstructed haplotypes in RAAS genes might be involved in the regulation of BP-lowering response to irbesartan in Chinese hypertensives.

Topics: Angiotensinogen; Antihypertensive Agents; Asian People; Biphenyl Compounds; Blood Pressure; China; Female; Haplotypes; Humans; Hypertension; Irbesartan; Male; Middle Aged; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Tetrazoles

The human angiotensinogen (hAGT) gene contains an A/G polymorphism at -217, and frequency of -217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant -217A almost always occurs with -532T, -793A, and -1074T, whereas variant -217G almost always occurs with -532C, -793G, and -1074G. Since allele -6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main haplotypes, -6A:-217A (AA) and -6A:-217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by approximately 40%, and plasma angiotensin II level is increased by approximately 50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Circadian Rhythm; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Renin; RNA, Messenger; Transcription, Genetic

Angiotensinogen gene (AGT) M235T polymorphism is associated with an increased risk of hypertension. It is unknown whether this mutation also leads to an increased risk of development of high blood pressure (BP) in pregnancy. The aim of this study was to investigate the association of this polymorphism with elevated blood pressure during pregnancy in a population of healthy Dutch women. We studied a randomly selected sample of 1,736 middle-aged women who participated in a prospective cohort study of 17,357 Dutch women. After excluding those who had never been pregnant or those with missing data, 429 women with and 921 women without a history of elevated BP during pregnancy remained for further analyses. History of hypertension in pregnancy was assessed using a questionnaire, and confirmed cases varied in severity from mild blood pressure elevation to pre-eclampsia. Individuals with the TT genotype were more likely to have had a history of elevated BP during pregnancy than those with the MM genotype (odds ratio [OR] = 1.43; 95% confidence interval [CI], 1.02-2.01; p = 0.04). In heterozygote individuals (MT) an increased risk was found, which did not reach statistical significance (OR = 1.24; 95% CI, 0.96-1.60; p = 0.11). Under both dominant and additive genetic models, the M235T polymorphism was associated with a history of elevated blood pressure during pregnancy, with ORs of 1.29 (95% CI, 1.01-1.64; p = 0.04) and 1.20 (95% CI, 1.02-1.42; p = 0.03), respectively. The findings of this study among Caucasian Dutch women, aged 49 to 70 years, demonstrated that the presence of the T allele of the M235T polymorphism in the AGT is associated with self-reported hypertensive disorders in pregnancy.

Topics: Aged; Angiotensinogen; Body Mass Index; Cohort Studies; Female; Humans; Hypertension; Middle Aged; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular; Prospective Studies; Risk Factors

Topics: Angiotensinogen; Animals; Blood Pressure; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Mice; Mice, Transgenic; Polymorphism, Genetic; Promoter Regions, Genetic; RNA, Messenger; Transcription, Genetic

The aim of this study is to examine whether the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms of the renin-angiotensin system (RAS) genes are associated with cardiovascular and renal-related risk factors in Mexican Americans. Study participants (N = 848) were genotyped by Taqman assays. Association analyses were performed by measured genotype approach. Of the phenotypes examined, the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms exhibited significant association with systolic blood pressure, glomerular filtration rate and body mass index, respectively. The data suggest that the polymorphisms examined in the RAS may modulate the risk factors associated with cardiovascular-renal disease.

Topics: Albuminuria; Alleles; Angiotensinogen; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; INDEL Mutation; Kidney Diseases; Male; Mexican Americans; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Texas

Topics: Aldosterone; Alleles; Angiotensinogen; Haplotypes; Humans; Hypertension; Polymorphism, Single Nucleotide; Renin

Hypertension results from the interaction of genetic and environmental factors. Since the renin-angiotensin and the natriuretic peptide systems contribute to blood pressure regulation, variations in the relative genes are candidates for the development of hypertension.. In 194 hypertensives and 304 controls of Hellenic origin, the possible association between the (CA)n repeat polymorphism of angiotensinogen (AGT), the 250 bp insertion/deletion (I/D) of angiotensin-converting enzyme (ACE), the tetranucleotide repeat polymorphism (TCTG)n of renin, and the (CT)n repeat polymorphism of the natriuretic peptide receptor A (NPRA) and hypertension was assessed.. No association between AGT and NPRA polymorphisms and hypertension was observed. The presence of ID or DD genotype of ACE was associated with an increased risk for hypertension compared with the II genotype (OR: 1.782 [95% CI: 1.032-3.077]), whereas the LL genotype of the renin gene was associated with a decreased risk compared with the SS genotype (OR: 0.174 [95% CI: 0.044-0.689]). However, after adjustment for confounding factors only the latter association remained.. In the present study conducted in a homogeneous Hellenic population, no associations between AGT,ACE, and NPRA gene polymorphisms and hypertension were found. The presence of a significant negative association between the LL polymorphism of the renin gene and hypertension requires further confirmation.

Topics: Aged; Angiotensinogen; Demography; Female; Gene Frequency; Genetic Predisposition to Disease; Greece; Humans; Hypertension; Male; Multivariate Analysis; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; White People

Knowledge of candidate gene polymorphisms in a population is useful for a variety of gene-disease association studies, particularly for some complex traits. A single nucleotide variant of the angiotensinogene gene (AGT M235T) and endothelial nitric oxide synthase gene (eNOS G894T) have been associated with hypertension.. A cross-sectional study consisting of 200 hypertensives and 198 age- and sex-matched controls was conducted. Subjects involved in this study were pure Malay for 3 generations. The AGT M235T and eNOS G894T polymorphisms were determined by PCR-RFLP method.. The distribution of M235T genotype in the population was 3.5% for MM, 30.4% for MT and 66.1% for TT. No significant difference was observed in genotype (chi(2)=1.30, p=0.52) and allele (chi(2)=0.87, p=0.35) frequencies among the 2 study group. In contrast, the distribution of genotypes for G894T was 74.1% for GG, 24.6% for GT and 1.3% for TT, respectively. Similarly, no significant difference was observed in genotype (chi(2)=0.94, p=0.33) and allele (chi(2)=0.60, p=0.44) frequencies between both study groups.. The AGT M235T and eNOS G894T polymorphisms are unlikely to play an important role in the pathogenesis of hypertension in Malays.

Topics: Adult; Aged; Angiotensinogen; Female; Genotype; Humans; Hypertension; Malaysia; Male; Middle Aged; Nitric Oxide Synthase Type III; Polymorphism, Genetic

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180+/-3 mm Hg) compared with dTGRs (208+/-5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110+/-3 and 119+/-6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT(c) intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Cardiomegaly; Connexin 43; Dietary Fats; Disease Models, Animal; Electrocardiography; Electrophysiology; Fatty Acids, Omega-3; Fumarates; Humans; Hypertension; Magnetocardiography; Male; Rats; Rats, Sprague-Dawley; Renin; Up-Regulation

We carried out comparison of distribution of alleles and genotypes of polymorphic loci of renin-angiotensin-aldosterone system genes: CYP11B2 (C-344T), AGT (Thr174Met) and REN (C-5434T, C-5312T, and A BglI G) and their combinations in two groups of patients with low renin forms of arterial hypertension (AH). Group 1 included 59 patients with low renin hyperaldosteronism (HA) at the background of glomerular zone adenoma and hyperplasia of adrenal cortex. Group 2 included 28 patients with low renin hypertensive disease characterized by normal level of aldosterone. Complex analysis of carriership of allele and genotype combinations evidence for the difference in genetic nature of two forms of low renin AH. Participation of CYP11B2 and REN and possibly AGT genes in development of low renin AH was convincingly shown.

Topics: Alleles; Angiotensinogen; Biomarkers; Cytochrome P-450 CYP11B2; DNA; Genetic Predisposition to Disease; Genotype; Humans; Hyperaldosteronism; Hypertension; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Prognosis; Renin

Identification of angiotensin-(1-12) as an intermediate precursor derived directly from angiotensinogen led us to explore whether the heart has the capacity to process angiotensin-(1-12) into biologically active angiotensin peptides. The generation of angiotensin I, angiotensin II, and angiotensin-(1-7) from exogenous angiotensin-(1-12) was evaluated in the effluent of isolated perfused hearts mounted on a Langendorff apparatus in three normotensive and two hypertensive strains: Sprague-Dawley, Lewis, congenic mRen2.Lewis, Wistar-Kyoto, and spontaneously hypertensive rats. Hearts were perfused with Krebs solution for 60 min before and after the addition of angiotensin-(1-12) (10 nmol/l). Angiotensin-(1-12) caused the rapid appearance of both angiotensin I and angiotensin II in the perfusate that peaked between 30 and 60 min of recirculation. Production of angiotensin-(1-7) from exogenous angiotensin-(1-12) rose steadily over the course of the 60-min experiment. These data directly demonstrate that angiotensin-(1-12) is a substrate for the formation of angiotensin peptides in cardiac tissue. This finding further suggests that this angiotensinogen-derived product is a previously unrecognized important precursor peptide to the renin-angiotensin system cascade.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Angiotensins; Animals; Animals, Genetically Modified; Disease Models, Animal; Hypertension; Male; Myocardium; Peptide Fragments; Perfusion; Rats; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Time Factors

Given that (1) the renin-angiotensin system (RAS) is compartmentalized within the central nervous system in neurons and glia (2) the major source of brain angiotensinogen is the glial cells, (3) the importance of RAS in the central control of blood pressure, and (4) nicotine increases the probability of development of hypertension associated to genetic predisposition; the objective of the present study was to evaluate the effects of nicotine on the RAS in cultured glial cells from the brainstem and hypothalamus of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Ligand binding, real-time PCR and western blotting assays were used to compare the expression of angiotensinogen, angiotensin converting enzyme, angiotensin converting enzyme 2 and angiotensin II type1 receptors. We demonstrate, for the first time, that there are significant differences in the basal levels of RAS components between WKY and SHR rats in glia from 1-day-old rats. We also observed that nicotine is able to modulate the renin-angiotensin system in glial cells from the brainstem and hypothalamus and that the SHR responses were more pronounced than WKY ones. The present data suggest that nicotine effects on the RAS might collaborate to the development of neurogenic hypertension in SHR through modulation of glial cells.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Brain Stem; Cells, Cultured; Dose-Response Relationship, Drug; Gene Expression; Hypertension; Hypothalamus; Neuroglia; Nicotine; Nicotinic Agonists; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger

Evaluation of relation between blood pressure (BP) and intraocular pressure (IOP) in two hypertensive rat strains: spontaneously hypertensive rats (SHR) and double transgenic (dTGR) (harboring human renin and angiotensinogen genes) rats, and in their normotensive control Wistar Kyoto and Sprague Dawley rats, respectively.. Each rat strain was divided into medicated and non-medicated groups. Medicated rats were treated orally with an angiotensin II receptor type 1 blocker. IOP was measured using a specific rebound tonometer and BP by a tail-cuff method. Both parameters were determined in conscious animals every second week. For comparison, at the end of the study, IOP was measured in conscious and anesthetized rats.. The baseline IOP was higher in hypertensive rats vs their normotensive controls. Eight weeks of treatment with an angiotensin type 1 receptor blocker did not prevent a slight increase in IOP, although it abolished the development of hypertension in SHR. The markedly elevated IOP was reduced in medicated and non-medicated dTGR animals during the short follow-up period. General anesthesia reduced IOP significantly.. The results suggest a positive relation between BP and IOP in hypertensive rats.

Topics: Anesthesia, General; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Humans; Hypertension; Intraocular Pressure; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin

The renin-angiotensin-aldosterone system (RAAS) plays a key role in blood pressure (BP) regulation. Among the components of the RAAS, the gene for the angiotensinogen (AGT) has been extensively studied. Several studies in different populations link Threonine instead of methionine at position 235 (M235T) and Methinine instead of threonine at position 174 (T174M) polymorphisms with essential hypertension. We were unable to study these polymorphisms in the Punjab population of Pakistan through routine Restriction Fragment Length Polymorphism (RFLP) method. Considering the importance of this region we decided to further investigate the 300 bp region harbouring these two single nucleotide polymorphisms.. Samples were derived from a larger study group. Polymerase chain reaction amplified fragments were subjected to either RFLP or Single Strand Conformation Polymorphism. Single stranded DNA showing mobility shift on denaturing gel were sequenced.. Sequencing confirmed the presence of M235T and T174M polymorphisms in the local population. In addition to these polymorphisms one additional base was found at an identical position in two of the samples. We found a substitution of G with C just adjacent to T174M polymorphism in all seven of our samples studied.. We report two additional bases and one substitution in the angiotensinogen gene of Punjab population. We also suggest that SsmI can be used for the investigation of T174M polymorphism.

Topics: Angiotensinogen; Base Sequence; Humans; Hypertension; Pakistan; Point Mutation; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational

A low expression of angiotensinogen in the heart has been construed as indicating a circulating uptake mechanism to explain the local effects of angiotensin II on tissues. The recent identification of angiotensin-(1-12) in an array of rat organs suggests this propeptide may be an alternate substrate for local angiotensin production. To test this hypothesis, tissues from 11-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 14) were stained with purified antibodies directed to the COOH terminus of angiotensin-(1-12). Robust angiotensin-(1-12) staining was predominantly found in ventricular myocytes with less staining found in the medial layer of intracoronary arteries and vascular endothelium. In addition, angiotensin-(1-12) immunoreactivity was present in the proximal, distal, and collecting renal tubules within the deep cortical and outer medullary zones in both strains. Preadsorption of the antibody with angiotensin-(1-12) abolished staining in both tissues. Corresponding tissue measurements by radioimmunoassay showed 47% higher levels of angiotensin-(1-12) in the heart of SHR compared with WKY rats (P < 0.05). In contrast, renal angiotensin-(1-12) levels were 16.5% lower in SHR compared with the WKY rats (P < 0.05). This study shows for first time the localization of angiotensin-(1-12) in both cardiac myocytes and renal tubular components of WKY and SHR. In addition, we show that increased cardiac angiotensin-(1-12) concentrations in SHR is associated with a small, but statistically significant, reduction in renal angiotensin-(1-12) levels.

Topics: Angiotensinogen; Animals; Antibody Specificity; Disease Models, Animal; Hypertension; Immunohistochemistry; Kidney Tubules; Male; Myocardium; Myocytes, Cardiac; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To explore the relationship between angiotensinogen (AGT) gene M235T and TCM syndrome type in essential hypertension (ET) patients.. The gene mutation frequency of AGT M235T in 168 ET patients and 42 nomotensive (NT) subjects were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.. There was a significant difference in AGT M235T gene mutation between patients of Gan-fire exuberant type and those of yin-yang deficiency type (P < 0.01), homozygote type TT appeared with higher frequency. Multivariate regression linear analysis demonstrated that the genotypes of AGT M235T was correlated with the prognosis of ET to a certain degree.. Gene mutation of AGT M235T may be associated with the genesis and development of ET, and the TCM syndrome type of ET has its own intrinsic molecular biological background.

Topics: Adult; Aged; Angiotensinogen; China; Diagnosis, Differential; Female; Humans; Hypertension; Male; Medicine, Chinese Traditional; Middle Aged; Multivariate Analysis; Mutation; Polymorphism, Genetic; Syndrome

This study investigated the relationship between iridological constitution and angiotensinogen (AGN) gene polymorphism in hypertensives. In addition to angiotensin converting enzyme gene, AGN genotype is also one of the most well studied genetic markers of hypertension. Furthermore, iridology, one of complementary and alternative medicine, is the diagnosis of the medical conditions through noting irregularities of the pigmentation in the iris. Iridological constitution has a strong familial aggregation and is implicated in heredity. Therefore, the study classified 87 hypertensive patients with familial history of cerebral infarction and controls (n = 88) according to Iris constitution, and determined AGN genotype. As a result, the AGN/TT genotype was associated with hypertension (chi2 = 13.413, p < .05). The frequency of T allele was 0.92 in patients and 0.76 in controls (chi2 = 13.159, p < .05). In addition, iridological constitutional classification increased the relative risk for hypertension in the subjects with AGN/T allele. These results suggest that AGN polymorphism predicts hypertension, and iridological constitutional classification enhances the risk for hypertension associated with AGN/T in a Korean population.

Topics: Adult; Angiotensinogen; Chi-Square Distribution; Connective Tissue; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Iris; Korea; Male; Medicine, East Asian Traditional; Middle Aged; Pigmentation; Polymorphism, Genetic; Predictive Value of Tests; Retrospective Studies; Risk Assessment

Sex differences in blood pressure are evident in experimental models and human subjects, yet the mechanisms underlying this disparity remain equivocal. The current study sought to define the extent of male-female differences in the circulating and tissue renin-angiotensin aldosterone systems (RAASs) of congenic mRen(2). Lewis and control Lewis rats. Male congenics exhibited higher systolic blood pressure than females [200 +/- 4 vs. 146 +/- 7 mmHg, P < 0.01] or Lewis males and females [113 +/- 2 vs. 112 +/- 2 mmHg, P > 0.05]. Plasma ANG II levels were twofold higher in male congenics [47 +/- 3 vs. 19 +/- 3 pM, P < 0.01] and fivefold higher than in male or female Lewis rats [6 +/- 1 vs. 6 +/- 1 pM]. ANG I levels were also highest in the males; however, plasma ANG-(1-7) was higher in female congenics. Male congenics exhibited greater circulating renin and angiotensin-converting enzyme (ACE) activities, as well as angiotensinogen, than female littermates. Renal cortical and medullary ANG II levels were also higher in the male congenics versus all the other groups; ANG I was lower in the males. Cortical ACE2 activity was higher in male congenics, yet neprilysin activity and protein were greater in the females, which may contribute to reduced renal levels of ANG II. These data reveal that sex differences in both the circulating and renal RAAS are apparent primarily in the hypertensive group. The enhanced activity of the RAAS in male congenics may contribute to the higher pressure and tissue injury evident in the strain.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Angiotensins; Animals; Animals, Genetically Modified; Blood Pressure; Disease Models, Animal; Female; Hypertension; Kidney; Male; Mice; Myocardium; Neprilysin; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Lew; Renin; Renin-Angiotensin System; Sex Factors

Renin-angiotensin system gene polymorphisms are associated with essential hypertension; angiotensinogen gene variants are considered potential genetic risk factors. The aim of this study was to investigate the contribution of the G-6A, T174M, M235T polymorphisms, genotypic interactions, and haplotypes toward essential hypertension.. In a case-control design, 810 consecutive ethnically matched unrelated individuals comprising 450 hypertensive patients and 360 controls were recruited. Genotyping by polymerase chain reaction-restriction fragment length polymorphism, genotypes combinations, and haplotypes analyses were performed. Plasma renin activity and plasma aldosterone concentration were measured.. The G-6A and M235T polymorphisms differed significantly (P = 0.007, odds ratio = 1.9, 95% confidence interval = 1.2-2.9; P < 0.0001, odds ratio = 3.7, 95% confidence interval = 2.3-5.7, respectively), wherein the -6A and 235T mutant alleles were over-represented in hypertensive patients (P < 0.0001, each). Genotypes combinations of six wild-type alleles versus the remaining resulted in odds ratio of 2.4 (P < 0.0001), further mutant alleles based combinations linearly correlated with systolic, diastolic, and mean blood pressure. Over-representation of the haplotypes, namely, A/174T, 174T/235T, A/235T, and A/174T/235T in hypertensive patients and G/174T, 174T/235M, G/235M, and G/174T/235M in controls, was identified as risk and protective haplotypes (P < 0.0001, each), respectively. The patients had significantly higher plasma aldosterone concentration and lower plasma renin activity (P < 0.0001), the former correlated with -6A and 235T alleles (P < 0.0001).. The interaction among G-6A, M235T and T174M polymorphisms in combinations or haplotypes emerged significant. These findings, conjoint with significant high plasma aldosterone concentration and low plasma renin activity, suggest low-renin hypertension in our study population.

Topics: Adult; Aldosterone; Angiotensinogen; Case-Control Studies; Female; Genotype; Haplotypes; Humans; Hypertension; India; Male; Middle Aged; Polymorphism, Genetic; Renin

The effect of polymorphisms of the RAS genes on the incidence of hypertension seems to be population-dependent. We studied the effects of the angiotensinogen T174M and M235T, angiotensin converting enzyme insertion/deletion (ACE I/D), and angiotensin II receptor 1 (AT1R) A1166C gene polymorphisms on the risk of hypertension among Hispanics. We selected all cases (n=256) and 257 age and sex group-matched controls from a random sample of free living Colombians (n=2,989). Logistic regression was used to estimate the independent effect of each polymorphism. All polymorphisms were in Hardy-Weinberg equilibrium in controls, with the exception of M235T, which showed a small excess of heterozygotes (p=0.005; disequilibrium coefficient, D=-0.0264). After adjustment for age, sex, body mass index, race, physical activity, family history of hypertension and cardiovascular disease, and other polymorphisms, subjects with the ACE DD genotype were 1.56 times (95% confidence interval [CI]: 1.05, 2.33) more likely to be hypertensive than carriers of the I allele (p=0.03). Also, adjusted systolic and diastolic blood pressure were 4.58 (95% CI: -0.39, 9.56) and 3.32 (95% CI: 0.78, 5.86) mmHg higher in DD homozygous individuals than in carriers of the I allele, respectively. Approximately 15% of the cases of hypertension in this population could be attributed to carriage of the DD genotype. None of the other polymorphisms was associated with either hypertension or blood pressure level. In conclusion, the ACE DD genotype appears to be an independent risk factor for development of hypertension and may explain a significant fraction of incident cases among Hispanics.

Topics: Angiotensinogen; Blood Pressure; Case-Control Studies; Colombia; Female; Gene Deletion; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Renin is the rate limiting enzyme in the renin-angiotensin (RA) system that regulates blood pressure and electrolyte balance. In this study, we investigated the renin inhibitory effect of a royal jelly (RJ)-derived peptide. A dipeptide YY was isolated from the digested fraction of RJ proteins by proteases and was found to inhibit human renin activity. The inhibition constant (Ki) of YY was estimated to be 10 microM when the Km was 0.16 microM using sheep angiotensinogen as the substrate. The peptide was observed to lower blood pressure in spontaneously hypertensive rats.

Topics: Angiotensinogen; Animals; Blood Pressure; CHO Cells; Chromatography, High Pressure Liquid; Cricetinae; Cricetulus; Dipeptides; DNA, Complementary; Enzyme-Linked Immunosorbent Assay; Fatty Acids; Female; Gene Transfer Techniques; Genetic Vectors; Humans; Hypertension; Insect Proteins; Molecular Structure; Peptide Hydrolases; Rats; Rats, Inbred SHR; Recombinant Proteins; Renin; Renin-Angiotensin System; Sheep

The influence of genetic contributors, such as common single nucleotide polymorphisms, on blood pressure and essential hypertension may vary with the gender. We used the power of a large, community-based sample to probe whether gender interacts with genes in contributing to extremes of blood pressure in 611 male and 656 female age-matched white Americans within the top and bottom 5th percentiles of blood pressure among >53 000 people in a health maintenance program. This approach has >90% statistical power to detect genes contributing as little as 3% to trait (blood pressure) variation. We scored approximately 60 000 genotypes in the subjects: 48 single nucleotide polymorphisms at 33 autosomal and 2 X-linked genes in adrenergic and renal pathways that regulate blood pressure. Six individual variants significantly affected blood pressure and demonstrated gene-by-gender interaction, yielding different effects of the single nucleotide polymorphism on blood pressure in males and females. In females, polymorphisms at beta(1)-adrenergic receptor and alpha(2A)-adrenergic receptor contributed to blood pressure, whereas in men, polymorphisms at beta(2)-adrenergic receptor and angiotensinogen were associated. An alpha(2A)-adrenergic receptor haplotype influenced blood pressure in women, whereas 2 angiotensinogen haplotypes were associated in men. We also detected gene-by-gene, gender-specific interactions (epistasis) in pathophysiological pathways. This study reveals gender-specific effects of single nucleotide polymorphisms, haplotypes, and gene-by-gene interactions that determine blood pressure in white Americans. Such genetic variants may define genetically and etiologically distinct subgroups of men and women with essential hypertension and may have implications for rational treatment selection.

Topics: Adult; Aged; Alleles; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Diastole; Epistasis, Genetic; Female; Genes, X-Linked; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Adrenergic; Sex Factors; United States; White People

Although polymorphisms in renin-angiotensin-aldosterone (RAA) system genes for angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 A/C1166), and aldosterone synthase (CYP11B2-344T/C) have been major targets for genetic investigation in association with essential hypertension (EH), the influence of these genetic factors is still to be determined. Because patients with young-onset EH are thought to possess a stronger genetic background than EH patients who show elevated BP relatively late in life, the targeted screening of hypertensive students in Tohoku University was completed for the selection of subjects for genetic investigation. Out of 16,434 students (12,794 males and 3,670 females) younger than 30, 22 students showed a high blood pressure (BP) (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively, on two occasions and more than 135 and/or 85 mmHg, respectively, at a third measurement during casual BP measurements at the Tohoku University Health Center. These 22 students were asked to measure their BP at home (HBP). Six of the students had a systolic HBP of more than 135 mmHg and/or a diastolic HBP of more than 85 mmHg, and these students subsequently received medical examinations at Tohoku University Hospital and were diagnosed with EH. Genotyping for the four major genetic polymorphisms mentioned above was performed on the six students with EH and on 12 of the remaining 16 students whose HBP was within the normal range (white coat hypertension: WCH). Neither the EH nor the WCH students showed a different distribution of genotypes and allelic frequencies, compared to those found in the general Japanese population. Hence, the present study suggests that none of the major genetic polymorphisms in the RAA system strongly influence the onset of EH.

Topics: Adolescent; Adult; Age of Onset; Alleles; Angiotensinogen; Asian People; Blood Pressure; Cytochrome P-450 CYP11B2; Female; Genetic Testing; Genotype; Humans; Hypertension; Japan; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The present study was designed to evaluate, in Wistar rats, the effect of high- or low-salt diet on the hemodynamic parameters and on the renal and lumbar sympathetic nerve activity. The renal gene expression of the renin angiotensin system components was also evaluated, aiming to find some correlation between salt intake, sodium homeostasis and blood pressure increase. Male Wistar rats received low (0.06% Na, TD 92141-Harlan Teklad), a normal (0.5% Na, TD 92140), or a high-salt diet (3.12% Na, TD 92142) from weaning to adulthood. Hemodynamic parameters such as cardiac output and total peripheral resistance, and the renal and lumbar sympathetic nerve activity were determined (n=45). Plasma renin activity, plasma and renal content of angiotensin (ANG) I and II, and the renal mRNA expression of angiotensinogen, renin, AT1 and AT2 receptors were also measured (n=24). Compared to normal- and low-salt diet-, high-salt-treated rats were hypertensive and developed an increase (P<0.05) in total peripheral resistance and lumbar sympathetic nerve activity. A decrease in renal renin and angiotensinogen-mRNAs and in plasma ANG II and plasma renin activity was also found in salt overloaded animals. The renal sympathetic nerve activity was higher (P<0.05) in low- compared to high-salt-treated rats, and was associated with an increase (P<0.05) in renal ANG I and II and with a decrease (P<0.05) in AT2 renal mRNA. Plasma ANG I and II and plasma renin activity were higher in low- than in normal-salt rats. Our results show that increased blood pressure is associated with increases in lumbar sympathetic nerve activity and total peripheral resistance in high-salt-treated rats. However, in low-salt-treated rats an increase in the renal sympathetic nerve was correlated with an increase in the renal content of ANG I and II and with a decrease in AT2 renal mRNA. These changes are probably in favor of the antinatriuretic response and the sodium homeostasis in the low-salt group.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Angiotensins; Animals; Gene Expression Regulation; Hypertension; Kidney; Male; Rats; Rats, Wistar; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Chloride, Dietary; Sympathetic Nervous System

Topics: Alleles; Amino Acid Substitution; Angiotensinogen; Blood Pressure; Calmodulin-Binding Proteins; Female; Genotype; Humans; Hypertension; Japan; Male; Middle Aged; Multivariate Analysis; Polymorphism, Genetic; Risk Factors; Sodium

The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease.. We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference.. We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke.. We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Carotid Artery Diseases; Cerebrovascular Disorders; Cohort Studies; Female; Genotype; Heterozygote; Humans; Hypertension; Male; Polymorphism, Genetic; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Stroke

Although progress in the genetics of essential hypertension may seem disappointing, it has considerable potential in defining research directions that will ultimately translate into clinical practice. The hypothesis that genetic variation at the angiotensinogen locus impacts on individual susceptibility to develop essential hypertension has motivated a substantial body of research by us and many others. We examine how analyses of the mechanisms by which variation in angiotensinogen expression may contribute to disease susceptibility and may have arisen in human populations have progressed in recent years. Although the objective of personalized medicine is still in the future, a genetic hypothesis based on human variation can uniquely empower functional genomics approaches to reach such an ultimate goal.

Topics: Angiotensinogen; Animals; Disease Models, Animal; Gene Expression; Genetic Predisposition to Disease; Humans; Hypertension; Mice; Nephrons; Rats; Renin-Angiotensin System

To identify the genetic contribution to the variation in blood pressure (BP) response to angiotensin-converting enzyme inhibitors (ACEIs), single-nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT), angiotensin receptor 1 (AGTR1), and angiotensin receptor 2 (AGTR2) genes were evaluated for their association with BP response to ACEI in Chinese patients with hypertension in a 2-stage design.. We selected 1447 hypertensive patients from a 3-year benazepril postmarket surveillance trial and genotyped them for 14 SNPs in the AGT, AGTR1, and AGTR2 genes. The AGT rs7079 (C/T) SNP (3'-untranslated region) was significantly associated with the response of diastolic BP to benazepril (diastolic BP response: -7.4 mm Hg for subjects with the CC genotype, -8.9 mm Hg for CA, and -10.1 mm Hg for AA; P=0.001). Although there was no association of individual SNPs in the AGTR1 gene, there was a graded response between common haplotypes and systolic BP reduction in the order of haplotype 2 (H2)/lack of haplotype 3 (non-H3) (-13.6 mm Hg) > non-H2/non-H3 (-10.9 mm Hg) > H3/non-H2 (-6.6 mm Hg) (P=0.004). The total variations in response to ACEI therapy that were explained by the AGT SNP and AGTR1 haplotype groups were 13% for systolic and 9% to 9.6% for diastolic BP, respectively.. AGT SNP rs7079 and AGTR1 haplotypes were associated with BP reduction in response to ACEI therapy in hypertensive Chinese patients. This will be useful in future studies, providing genetic markers to predict the hypertensive response to ACEI therapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Benzazepines; Blood Pressure; Female; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2

To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes.. All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the alpha-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein beta3 (GNB3) genes were typed.. Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06).. Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensinogen; Blood Pressure; Cohort Studies; Female; Genetic Testing; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Inheritance Patterns; Male; Middle Aged; Multifactorial Inheritance; Netherlands; Pedigree; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Sterol Regulatory Element Binding Protein 1

Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and beta-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or beta-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension , aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in The Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of beta-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cohort Studies; Comorbidity; Female; Genetic Predisposition to Disease; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Netherlands; Pharmacogenetics; Polymorphism, Genetic; Prospective Studies; Renin-Angiotensin System; Risk Factors; Stroke

Polymorphisms of the angiotensinogen (Agt) gene may affect blood pressure. We used a mouse model to test for the role of the Agt genotype in low-renin or high-renin forms of hypertension. Mice bearing one, two, three, or four copies of the Agt gene underwent renal artery clipping to induce high-renin two-kidney, one-clip renovascular hypertension (2K1C), or uninephrectomy, salt loading, and application of deoxycorticosterone-acetate (DOCA) pellets to induce low-renin mineralocorticoid hypertension. Appropriate control animals were also studied. Blood pressure was measured by tail cuff as well as by direct intra-arterial recordings. There was a small effect of the Agt genotype on baseline blood pressure before induction of hypertension. The extent of 2K1C hypertension was not affected by the genotype. In contrast, there was a marked gene-dose effect on DOCA-hypertension (21.2 mmHg over all genotypes). Treatment of DOCA mice with the angiotensin II type 1 receptor antagonist abolished the genotype effect on blood pressure and left ventricular hypertrophy. There was a trend towards less suppression of endogenous aldosterone by DOCA treatment with increasing number of Agt gene copies. We conclude that the Agt genotype exerts a marked effect on blood pressure in a low-renin form of hypertension but no effect in the face of stimulated renin, at least in mice.

Topics: Angiotensinogen; Animals; Disease Models, Animal; Genotype; Hypertension; Kidney; Mice; Mice, Inbred C57BL; Renin-Angiotensin System

Topics: Angiotensinogen; Blood Pressure; Humans; Hypertension; Renin-Angiotensin System; Sodium Chloride, Dietary; Sodium, Dietary

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Biological Evolution; Blood Pressure; Humans; Hypertension; Renin; Renin-Angiotensin System; Sodium, Dietary

Rats harboring the human renin and angiotensinogen genes (dTGR) feature angiotensin (ANG) II/hypertension-induced cardiac damage and die suddenly between wk 7 and 8. We observed by electrocardiogram (ECG) telemetry that ventricular tachycardia (VT) is a common terminal event in these animals. Our aim was to investigate electrical remodeling. We used ECG telemetry, noninvasive cardiac magnetic field mapping (CMFM) at wk 5 and 7, and performed in vivo programmed electrical stimulation at wk 7. We also investigated whether or not losartan (Los; 30 mg x kg(-1) x day(-1)) would prevent electrical remodeling. Cardiac hypertrophy and systolic blood pressure progressively increased in dTGR compared with Sprague-Dawley (SD) controls. Already by wk 5, untreated dTGR showed increased perivascular and interstitial fibrosis, connective tissue growth factor expression, and monocyte infiltration compared with SD rats, differences that progressed through time. Left-ventricular mRNA expression of potassium channel subunit Kv4.3 and gap-junction protein connexin 43 were significantly reduced in dTGR compared with Los-treated dTGR and SD. CMFM showed that depolarization and repolarization were prolonged and inhomogeneous. Los ameliorated all disturbances. VT could be induced in 88% of dTGR but only in 33% of Los-treated dTGR and could not be induced in SD. Untreated dTGR show electrical remodeling and probably die from VT. Los treatment reduces myocardial remodeling and predisposition to arrhythmias. ANG II target organ damage induces VT.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiac Pacing, Artificial; Cardiomegaly; Connexin 43; Death, Sudden, Cardiac; Disease Models, Animal; Electrocardiography; Heart Conduction System; Hypertension; Losartan; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Shal Potassium Channels; Tachycardia, Ventricular; Telemetry; Time Factors; Ventricular Remodeling

In order to investigate the contribution of candidate genes in the RAAS in pathogenesis of EAH, we analysed the M235T polymorphism of the angiotensinogen gene, and the I/D polymorphism of ACE gene in a group of adult Caucasians (Slovene population) with EAH. Four-hundred and thirteen unrelated subjects with the diagnosis of EAH were included in the association study and they were compared to 414 subjects with normal blood pressure (the control group). The M235T angiotensinogen genotype distribution in patients with EAH (TT = 23.2%, MT = 48.7%, MM = 28.1%) did not differ from genotype distribution in controls (TT = 21.1%, MT = 49.0%, MM = 29.9%), and the TT genotype was not associated with EAH (OR 1.1; 95% CI 0.7-1.7; P = 0.6). Moreover, The I/D ACE genotype distribution in patients with EAH (DD = 32.0%, ID = 48.2%, II = 19.8%) did not differ from genotype distribution in controls (DD = 32.2%, ID = 49.0%, II = 18.8%), and the DD genotype was not associated with EAH (OR 1.0; 95% CI 0.7-1.3; P = 0.9). In conclusion, we failed to demonstrate that the M235T angiotensinogen polymorphism and the ACE I/D polymorphism were genetic markers for EAH in adult Caucasians.

Topics: Angiotensinogen; Case-Control Studies; Genotype; Humans; Hypertension; Methionine; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Threonine; White People

Evidence shows that an elevated pulse pressure (PP) may lead to an increased risk of cardiovascular morbidity and mortality. There is also evidence that PP is a sexually dimorphic trait, and that genetic factors influence inter-individual variation in PP. The aim of this project was to assess the genotype-by-sex interaction on PP in a sample of mostly hypertensive African American and White participants using candidate genes involved in the renin-angiotensin-aldosterone system. Subjects were participants in the HyperGEN Study, including men (43%) and women (57%) over the age of 55 years (mean age = 65). Candidate gene polymorphisms used were ACE insertion/deletion (1,789 subjects genotyped) and AGT-M235T (1,800 subjects genotyped). We employed linear regression methods to assess the genotype-by-sex interaction. For ACE, genotype-by-sex interaction on PP was detected (P = 0.04): the "D/D" genotype predicted a 2.2 mmHg higher pulse pressure among women, but a 1.2 mmHg lower PP among men, compared to those with an "I" allele, after adjusting for age, weight, height, ethnicity, and antihypertension medication use. A similar interaction was found for systolic blood pressure. The genotype-by-sex interaction was consistent across ethnicity. The interaction was evident among those on antihypertensive medications (P = 0.05), but not among those not taking such medications (P = 0.55). In our analysis of AGT, no evidence of a genotype-by-sex interaction affecting PP, SBP, or DBP was detected. This evidence for a genotype-by-sex interaction helps our understanding of the complex genetic underpinnings of blood pressure phenotypes.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Epidemiologic Studies; Female; Gene Frequency; Genotype; Humans; Hypertension; INDEL Mutation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Sex Characteristics

The renin-angiotensin-aldosterone system (RAAS) is important for the development of essential hypertension, and many antihypertensive drugs target it. This study was undertaken to determine whether polymorphisms in the renin-angiotensin-aldosterone system are related to the blood pressure (BP) response to diuretic treatment in a Chinese Han ethnic population.. Fifty-four patients with essential hypertension received hydrochlorothiazide (12.5 mg, once daily) as monotherapy for four weeks. Seven polymorphisms in RAAS genes were genotyped by gene chip technology. The relationship between these polymorphisms and the change in blood pressure was observed after the 4-week treatment.. The patients with angiotensinogen (AGT) -6G allele showed a greater reduction in diastolic BP (P=0.025) and mean BP (P=0.039) than those carrying AA genotype. Patients carrying aldosterone synthase (CYP11B2) CC genotype exhibited a greater BP reduction than those carrying CT and TT genotypes (systolic BP: P=0.030; diastolic BP: P=0.026; mean BP: P=0.003). In addition, patients with a combination of CYP11B2 CC genotype and angiotensin converting enzyme (ACE) D allele might have a more pronounced reduction of systolic BP than those with any other genotypic combinations of the two genes (P=0.007).. AGT-6G allele, CYP11B2 -344CC genotype and its combination with ACE D allele are associated with BP response to hydrochlorothiazide treatment. Larger studies are warranted to validate this finding.

Topics: Aged; Angiotensinogen; Cytochrome P-450 CYP11B2; Female; Genotype; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide

Reduced uterine perfusion initiated in late gestation in the rat results in intrauterine growth restriction (IUGR) and development of hypertension by 4 wk of age. We hypothesize that the renin angiotensin system (RAS), a regulatory system important in the long-term control of blood pressure, may be programmed by placental insufficiency and may contribute to the etiology of IUGR hypertension. We previously reported that RAS blockade abolished hypertension in adult IUGR offspring; however, the mechanisms responsible for the early phase of hypertension are unresolved. Therefore, the purpose of this study was to examine RAS involvement in early programmed hypertension and to determine whether temporal changes in RAS expression are observed in IUGR offspring. Renal renin and angiotensinogen mRNA expression were significantly decreased at birth (80 and 60%, respectively); plasma and renal RAS did not differ in conjunction with hypertension (mean increase of 14 mmHg) in young IUGR offspring; however, hypertension (mean increase of 22 mmHg) in adult IUGR offspring was associated with marked increases in renal angiotensin-converting enzyme (ACE) activity (122%) and renal renin and angiotensinogen mRNA (7-fold and 7.4-fold, respectively), but no change in renal ANG II or angiotensin type 1 receptor. ACE inhibition (enalapril, 10 mg x kg(-1) x day(-1), administered from 2 to 4 wk of age) abolished hypertension in IUGR at 4 wk of age (decrease of 15 mmHg, respectively) with no significant depressor effect in control offspring. Therefore, temporal alterations in renal RAS are observed in IUGR offspring and may play a key role in the etiology of IUGR hypertension.

Topics: Angiotensinogen; Animals; Birth Weight; Blood Pressure; Body Weight; Female; Hypertension; Kidney; Male; Peptidyl-Dipeptidase A; Placental Insufficiency; Pregnancy; Rats; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; RNA, Messenger; Sex Factors

To test the hypothesis that genetically determined alterations of the renin-angiotensin system are associated with hypertensive disorders in pregnancy.. A genetic association study was conducted at the obstetrics department of the Charité university hospital, Berlin, Germany. A total of 1068 Caucasian women were consecutively included after delivery and genotyped for the angiotensinogen M235T polymorphism and the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism.. Women homozygous for the angiotensinogen T allele have significantly elevated mean systolic and diastolic blood pressures in the third trimester (118.4 +/- 1.1/71.5 +/- 0.7 versus 116.9 +/- 0.3/70.4 +/- 0.2 mmHg, n = 128 versus 940; P < 0.05). This finding is especially pronounced in the subgroup of primigravid women. The ACE polymorphism is not associated with blood pressure during pregnancy. None of the polymorphisms is associated with urinary protein excretion or oedema during pregnancy. Maternal polymorphisms do not influence fetal growth and birth weight. There is, however, an interesting trend towards an increased incidence of circulatory system malformations in newborns carrying alleles that are known to be associated with decreased intrinsic renin-angiotensin system activity.. We demonstrate for the first time in a large Caucasian population that a common maternal polymorphism of the angiotensinogen gene is related to a blood pressure increase during pregnancy. The angiotensinogen M235T polymorphism might contribute to the multifactorial pathogenesis of gestational hypertension and pre-eclampsia.

Topics: Amino Acid Substitution; Angiotensinogen; Blood Pressure; Case-Control Studies; DNA Transposable Elements; Female; Humans; Hypertension; Infant, Newborn; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Proteinuria; Sequence Deletion

Hypertensive mice that express the human renin and angiotensinogen genes are used as a model for human hypertension because they develop hypertension secondary to increased renin-angiotensin system activity. Our study investigated the cellular localization and distribution of COX-1, COX-2, mPGES-1, and mPGES-2 in organ tissues from a mouse model of human hypertension. Male (n = 15) and female (n = 15) double transgenic mice (h-Ang 204/1 h-Ren 9) were used in the study. Lung, kidney, and heart tissues were obtained from mice at necropsy and fixed in 10% neutral buffered formalin followed by embedding in paraffin wax. Cut sections were stained immunohistochemically with antibodies to COX-1, COX-2, mPGES-1, and mPGES-2 and analyzed by light microscopy. Renal expression of COX-1 was the highest in the distal convoluted tubules, cortical collecting ducts, and medullary collecting ducts; while proximal convoluted tubules lacked COX-1 expression. Bronchial and bronchiolar epithelial cells, alveolar macrophages, and cardiac vascular endothelial cells also had strong COX-1 expression, with other renal, pulmonary, or cardiac microanatomic locations having mild-to-moderate expression. mPGES-2 expression was strong in the bronchial and bronchiolar epithelial cells, mild to moderate in various renal microanatomic locations, and absent in cardiac tissues. COX-2 expression was strong in the proximal and distal convoluted tubules, alveolar macrophages, and bronchial and bronchiolar epithelial cells. Marked mPGES-1 was present only in bronchial and bronchiolar epithelial cells; while mild-to-moderate expression was present in other pulmonary, renal, or cardiac microanatomic locations. Expression of these molecules was similar between males and females. Our work suggests that in hypertensive mice, there are (a) significant microanatomic variations in the pulmonary, renal, and cardiac distribution and cellular localization of COX-1, COX-2, mPGES-1, and mPGES-2, and (b) no differences in expression between genders.

Topics: Angiotensinogen; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Female; Humans; Hypertension; Immunohistochemistry; Intramolecular Oxidoreductases; Kidney; Lung; Male; Mice; Mice, Transgenic; Microsomes; Myocardium; Prostaglandin-E Synthases; Renin

Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with (35)S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT(1A)] receptors). Resting arterial pressure and heart rate were higher in SHR(S) (177+/-2 mm Hg, 357+/-12 bpm versus 121+/-1 mm Hg, 320+/-9 bpm in WKY(S); P<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (-10%) in both groups. Training-induced blood pressure fall (-6.3%) was observed only in SHR(T). In SHR(S) (versus WKY(S)) AT(1A) and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT(1A) and Aogen, respectively; P<0.05) but unchanged in the gracilis nucleus. Training did not change AT(1A) expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR(T) (P<0.05 versus SHR(S), with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41; r=0.55; P<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.

Topics: Angiotensinogen; Animals; Blood Pressure; Heart Rate; Hypertension; Male; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Solitary Nucleus

Topics: Angiotensinogen; GTP-Binding Proteins; Humans; Hypertension; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Receptors, Leptin

We studied the effects of extremely low-dose human renin inhibition (aliskiren) with low angiotensin II receptor blockade (losartan) in a novel double-transgenic rat model harbouring both human renin and angiotensinogen genes. We found that low-dose aliskiren and low-dose losartan effectively reduced mortality and target-organ damage with minimal, non-significant, effects on blood pressure (BP). Our data suggest that renin-angiotensin system (RAS) inhibition ameliorates target-organ damage in an Ang II-driven model of hypertension. Direct renin inhibition is equally efficacious in this regard. Our study does not fully answer the question of BP-lowering versus RAS inhibition. This question is important and was at least partially addressed with our low-dose model.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Fumarates; Humans; Hypertension; Rats; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System

Placental insufficiency in the rat results in intrauterine growth restriction and development of hypertension in prepubertal male and female growth-restricted offspring. However, after puberty, only male growth-restricted offspring remain hypertensive, whereas female growth-restricted offspring stabilize their blood pressure to levels comparable to adult female controls. Because female rats reach their maximum levels of estrogen at puberty, we hypothesize that estrogen may be a factor involved in the stabilization of blood pressure in adult female growth-restricted offspring. At 10 weeks of age, female control and growth-restricted offspring underwent ovariectomy or sham surgery and insertion of a telemetry probe. Mean arterial pressure was similar at 16 weeks of age between control (123+/-4 mm Hg) and growth-restricted offspring (122+/-2 mm Hg); however, ovariectomy led to a significant increase in blood pressure in growth-restricted offspring (140+/-2 mm Hg; P<0.05 versus intact counterpart) with no significant effect in controls (124+/-1 mm Hg). Estrogen replacement by subcutaneous minipellet initiated at 14 weeks of age in a subset of ovariectomized control and growth-restricted offspring reversed the effect of ovariectomy on blood pressure in growth-restricted offspring at 16 weeks of age (111+/-3 mm Hg; P<0.05 versus ovariectomized counterpart); renin angiotensin system blockade also abolished ovariectomy-induced hypertension in female growth-restricted offspring (106+/-2 mm Hg; P<0.05 versus ovariectomized counterpart). Therefore, sex differences are observed in this model of fetal programmed hypertension, and results from this study suggest that estrogen contributes to normalization of blood pressure in adult female growth-restricted offspring.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Birth Weight; Blood Pressure; Estradiol; Estrogens; Female; Fetal Development; Fetal Growth Retardation; Hypertension; Kidney; Male; Peptidyl-Dipeptidase A; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger; Sex Characteristics; Sexual Maturation

The activity of the renin-angiotensin system influences blood pressure (BP) and cardiovascular structure in humans. Therefore, we questioned whether left-ventricular (LV) structure and function are influenced by the -20 A/C variant of the angiotensinogen (AGT) gene in young normotensive or mildly hypertensive patients.. A homogenous cohort of young, male, white subjects (n = 214) with normal or mildly elevated BP never treated in the past, or on current cardiovascular medication, were recruited. All subjects were genotyped by single-strand conformational polymorphism analysis and DNA sequencing for the -20 A/C polymorphism of the AGT gene. Ambulatory BP was assessed over 24 h by an automatic portable device. Left-ventricular structure and function were determined by two-dimensional guided M-mode echocardiography.. The frequency of subjects homozygous for the -20 A allele was 73.4%, and the frequency for those with at least one copy of the -20 C allele was 26.6%. In hypertensive subjects with at least one copy of the -20 C allele, posterior (P = .027) and septal (P = .021) wall thickness, as well as LV mass (P = .027), were greater than in hypertensive subjects homozygous for the -20 A allele. Moreover, LV functional parameters such as midwall fractional fiber shortenings (P = .021) and the velocity of circumferential fiber shortening (P = .013) were decreased in hypertensive subjects with at least one copy of the -20 C allele, compared with subjects homozygous for the -20 A allele. Confounding factors of LV structure and systolic function, such as age, height, body mass index, physical activity, ambulatory 24-h BP, and sodium intake, were similar between the -20 A/C variants of the AGT gene in both normotensive and hypertensive subjects.. In young, mildly hypertensive subjects, cardiac structure and function are modulated by the -20 A/C gene variant of the AGT.

Topics: Adult; Angiotensinogen; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Polymorphism, Genetic; Ventricular Function, Left

Hypertension and left ventricular hypertrophy (LVH) are important causes of morbidity and mortality in the population. Angiotensinogen (AGT) M235T polymorphism has been associated with LVH, left ventricular dimensions, coronary artery disease and antihypertensive drug response in previous studies. We examined relationship between AGT M235T polymorphism and echocardiographic left ventricular indices in a Turkish population of treated hypertensive patients with normal coronary arteries.. In this cross-sectional study a Turkish population of 92 hypertensive patients treated in our outpatient clinic were enrolled. All patients had normal coronary angiographic examinations. Genotypes for AGT M235T were determined from peripheral leukocytes. Left ventricular dimensions, mass and function indices, after adjustment for clinical covariates were analyzed by multiple regression analysis according to genotypes.. Genotype frequencies for AGT M235T were MM-24.7%, MT-52.8% and TT-22.5%. Left ventricular end-systolic (LVES) dimensions for AGT M235T MM, MT, TT genotypes were 17.9+/-4.2 mm, 19.4+/-6.2 mm, and 16.4+/-2.9 mm, respectively (p=0.08). Angiotensinogen M235T TT genotype showed a trend towards a lower LVES dimension but results were not statistically significant. Left ventricular ejection fractions for AGT M235T MM, MT, TT subgroups were 61.3+/-15.0%, 59.4+/-14.0%, and 67.8+/-8.5%, respectively (p=0.07). Angiotensinogen M235T TT genotype showed a tendency towards lower left ventricular mass index but results were not statistically significant. None of the AGT M235T genotypes predicted left ventricular dilatation, mass or function in treated hypertensive patients with normal coronary arteries.. Angiotensinogen M235T polymorphism was not useful to predict left ventricular mass, function, hypertrophy or dilatation in a small population of treated Turkish hypertensive patients with normal coronary arteries.

Topics: Angiotensinogen; Coronary Vessels; Cross-Sectional Studies; Echocardiography; Female; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Polymorphism, Genetic; Predictive Value of Tests; Turkey; White People

The adverse association between blood pressure and carotid artery intima-media thickness (IMT), a surrogate measure of subclinical atherosclerosis, is well-known. However, whether the G-6A polymorphism of the angiotensinogen (AGT) gene, a candidate gene of hypertension and vascular remodeling, modulates this relationship is unknown.. In 662 white and black subjects aged 25 to 43 years (73.4% white, 39.7% male), common carotid IMT was measured by B-mode ultrasonography.. The variant A-6 allele frequency was higher in blacks than in whites (0.850 v 0.448, P < .0001). In a bivariate analysis, there were no differences in mean arterial blood pressure and common carotid IMT between carriers and noncarriers of the G allele in whites, blacks, or the total sample, after adjusting for gender, age, and race. In a multivariable regression analysis that included the status of the G allele (carriers versus noncarriers) along with gender, age, mean arterial blood pressure, body mass index, LDL cholesterol, triglycerides:HDL cholesterol ratio, homeostasis model assessment of insulin resistance, smoking, and race (in the total sample), mean arterial blood pressure was significantly and adversely associated with common carotid IMT in whites, blacks, and the total sample. This adverse positive relationship between mean arterial blood pressure and common carotid IMT was noted among noncarriers but not carriers of the G allele (comparison of slopes, P = .02) in the total sample. Although the interaction was not significant (P = .2 and P = .05 in whites and blacks, respectively), a trend similar to that in the total sample was found in both races.. In a recessive manner, the genetic variant (G-6A) of the AGT gene modulates the association between blood pressure and carotid IMT in young adults.

Topics: Adult; Angiotensinogen; Atherosclerosis; Black People; Blood Pressure; Carotid Artery, Common; Cross-Sectional Studies; Female; Gene Frequency; Genotype; Humans; Hypertension; Louisiana; Male; Polymorphism, Single Nucleotide; Risk Factors; Tunica Intima; Tunica Media; Ultrasonography; White People

We previously reported that a high-sodium diet activates the local renin-angiotensin-aldosterone system (RAAS) in cardiovascular tissues of Dahl salt-sensitive hypertensive (DS) rats. Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of blood pressure (BP) and cardiac function. The effect of blockade of aldosterone or angiotensin II (Ang II) on cardiac angiotensinogen and ACE2 in DS rats is unknown.. The BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), heart weight, endothelium-dependent relaxation (EDR), and messenger RNA (mRNA) levels of collagen III, angiotensinogen, ACE, and ACE2 in the heart were measured in DS rats and in Dahl salt-resistant (DR) rats fed high or low salt diets. The rats were treated orally with or without eplerenone (100 mg/kg/d), candesartan (10 mg/kg/d), or both drugs combined for 8 weeks.. A high salt diet increased BP (140%), heart/body weight (132%), and collagen III mRNA levels (146%) and decreased PRA and PAC concomitant with increased expression of cardiac angiotensinogen mRNA and decreased mRNA levels of ACE2 in DS rats. Eplerenone or candesartan significantly decreased the systolic BP from 240 +/- 5 mm Hg to 164 +/- 4 mm Hg or to 172 +/- 10 mm Hg, respectively (P < .05). Eplerenone or candesartan partially improved heart/body weight and cardiac fibrosis, improved EDR and decreased cardiac ACE and angiotensinogen mRNA levels in DS rats. Candesartan increased ACE2 mRNA levels in the heart. Combination therapy normalized BP and further improved cardiac hypertrophy, fibrosis, and EDR.. In DS rats, blockade of aldosterone or Ang II protects cardiac hypertrophy and fibrosis by inactivation of the local RAAS in the heart.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Cardiomegaly; Endothelium, Vascular; Eplerenone; Fibrosis; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Spironolactone; Tetrazoles

To investigate the relationship of four single nucleotide polymorphism (SNP) haplotypes in the angiotensinogen (AGT) gene to the primary hypertension with or without cerebral infarction in the Li nationality of Hainan, China.. Total 300 subjects were allocated into three different groups: Group 1, 100 patients who have primary hypertension; Group 2, 100 patients who have primary hypertension with cerebral infarction; and control group, 100 healthy individuals. The genotypes of all subjects were determined by PCR-sequencing to analyze the four polymorphisms at position -152 (G-A), -20 (A-C), -18 (C-T), and -6 (A-G) in the promoter region of AGT.. The frequencies of CT genotype of AGT-18 and T allele in Group 1 (P = 0.003, P = 0.004) and Group 2 (P = 0.002, P = 0.002) were both significantly higher than in healthy controls. The frequency of G allele of AGT-6 was significantly higher in Group 2 than in the control group (P = 0.016), while there is no significant difference between Group 1 and the control. Haplotype analysis revealed that H6 haplotype frequency which included -20C and -6G was significantly increased in Group 2 (P = 0.003) compared with the control group, while H5 haplotype frequency which included -20C and -18T was significantly increased in Group 1 (P = 0.006) versus the control.. The -20 (A-C) and -18 (C-T) of the AGT may play an important role in pathogenesis of primary hypertension; and -20 (A-C), -18 (C-T), and -6 (A-G) may be the genetic risk factors for the onset of primary hypertension with cerebral infarction in the Li nationality of Hainan, China.

Topics: Angiotensinogen; Cerebral Infarction; China; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

Steroid refractory acute rejection (SRAR) is a major vital factor in renal transplantation recipients. The pathogenesis of SRAR may involve both immune and non-immune mechanisms. A decreased renal allograft function has also been associated with increased activity of renin-angiotensin-aldosterone system (RAS), which may be genetically determined. A total 206 renal transplant recipients, 116 males and 90 females, were included. The effects of gene polymorphisms of the four components of RAS including angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AT1R), and aldosterone synthase (CYP11B2) were investigated in 19 cases of renal transplant patients with SRAR. The association between SRAR and the activating antibodies targeting the AT1R were also investigated. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. Our results showed that renal allograft recipients with SRAR had significantly higher occurrences of the DD genotype of ACE and CC genotype of AT1R than recipients without SRAR. The other genetic polymorphisms of the RAS were not associated with SRAR. Activating antibodies targeting the AT1R were detected in the sera from 14 SRAR victims with malignant hypertension and without anti-HLA antibodies. This study provides evidence that determination before transplantation of the polymorphism of the gene encoding components of RAS may help identify patients who are at risk for SRAR. The detection of the antibodies of AT1R may contribute to the prevention of SRAR.

Topics: Adult; Angiotensinogen; Cytochrome P-450 CYP11B2; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Many previous studies have investigated whether there is an association between genotypes at the angiotensinogen (AGT) gene and hypertensive status, but few have incorporated quantitative data. Although meta-analyses support a possible effect of AGT variants on blood pressure (BP), substantial unexplained between-study heterogeneity has been observed. We hypothesized that a primary effect of AGT variants on arterial stiffness (and thus pulse pressure) might explain such heterogeneity, and tested for such an effect in a family study.. We studied 1425 individuals from 248 families ascertained through a proband with essential hypertension. BP was measured using 24 h ambulatory monitoring, and polymorphisms of the AGT gene that had been previously associated with hypertension and/or plasma angiotensinogen levels were typed. Pulse pressure was used as a measurement of arterial stiffness.. We observed a highly significant association between genotypes at the AGT C-532T polymorphism and pulse pressure (p = 0.00006). Each T allele was associated with a 5% lower pulse pressure (that is, an additive effect). This resulted from opposing genotypic effects to (slightly) lower systolic BP and (slightly) elevate DBP.. These results suggest that genetic variation at the angiotensinogen locus may primarily affect arterial stiffness, and therefore pulse pressure. The heterogeneity between previous genetic studies of AGT and hypertension status could in part be explained by this finding, since case selection criteria based on systolic BP, diastolic BP, or both would result in different levels of selection for the -532T allele.

Topics: Adult; Alleles; Angiotensinogen; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Cohort Studies; Confounding Factors, Epidemiologic; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Pulse; Regression Analysis

Topics: Angiotensinogen; Antihypertensive Agents; Coronary Vessels; Female; Genetic Predisposition to Disease; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Polymorphism, Genetic; Turkey; White People

The human angiotensinogen gene (AGT) is a promising candidate for an essential hypertension-susceptibility gene. We aimed to explore the single-locus, haplotype and epistasis patterns of three polymorphisms of AGT (A-20C, A-6G and M235T) and their relation to the risk of essential hypertension in a Tibetan population. The three polymorphisms were genotyped in 333 essential hypertension patients and 235 healthy controls on the basis of a door-to-door cross-sectional study. Genotyping was performed using polymerase chain reaction (PCR)-restriction fragment length polymerase (RFLP) and direct sequencing techniques. The data were analyzed using the EH/EH+ program and the multifactor dimensionality reduction (MDR) method. Our single-locus analysis revealed that except for a marginal, significant association of A-20C allele distribution, no significant association between genotype and allele distributions of the A-20C, A-6G, or M235T polymorphism of AGT and essential hypertension was found. In haplotype analysis, we found that the H(1) haplotype may be the risk-conferring factor for hypertension, even after the Bonferroni correction. In epistasis analysis, we selected the final best model, which included the A-20C and A-6G polymorphisms with a strong synergistic effect. This model had a maximum testing accuracy of 0.564 and a maximum cross validation consistency of 10 out of 10 (p=0.001). The present study thus provides evidence of a strong synergistic effect of the A-20C and A-6G polymorphisms of AGT, which were not found to be associated with essential hypertension in the single-locus analysis. Moreover, we have proposed a promising data-mining analytical method using the open-source MDR software package for detecting and characterizing gene-gene interactions.

Topics: Adult; Aged; Angiotensinogen; Epistasis, Genetic; Female; Genotype; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Genetic; Tibet

Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT1A receptors and Rho-kinase. Basilar arteries (baseline diameter approximately 130 microm) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by approximately 85% in mice deficient in expression of AT1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R+) and angiotensinogen (A+). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R+A+ mice (P<0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R+A+ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R+A+ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.

Topics: Angiotensin II; Angiotensinogen; Animals; Cerebral Arteries; Cerebrovascular Circulation; Endothelium, Vascular; Female; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Serine-Threonine Kinases; Receptor, Angiotensin, Type 1; Renin; rho-Associated Kinases; Sex Factors; Superoxides; Vasoconstriction

Obesity is associated with hypertension and other cardiovascular diseases especially in the African-American population. Human angiotensinogen (AGT) gene has seven single nucleotide polymorphisms (SNPs) in 1.2 kb region of its promoter. Recent studies have shown that variant -217A is associated with hypertension in African-American and Chinese population. Nucleotide sequence of the hAGT gene has shown that variant -217A almost always occurs with variants -532T, -793A and -1074T (forming haplotype AAT) and variant -217G almost always occurs with variants -532C, -793G and -1074G (forming haplotype GGG). Since hAGT gene is expressed in the adipose tissue and its expression in this tissue may play a role in hypertension, we have analyzed the role of haplotypes AAT and GGG on the expression of this gene in adipocytes. We show here that a reporter construct with haplotype AAT of the hAGT gene has increased promoter activity on transient transfection in pre-adipocytes and differentiated adipocytes as compared to the reporter construct containing GCGG haplotype. Increased expression of the AGT gene containing haplotype AAT in the liver and adipocytes may be a contributing factor for hypertension.

Topics: 3T3-L1 Cells; Adipocytes; Angiotensinogen; Animals; Dexamethasone; Haplotypes; Humans; Hypertension; Mice; Obesity; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Recombinant Fusion Proteins; Transcription, Genetic; Transfection

Angiotensinogen (ANG) is the sole substrate of the renin-angiotensin system (RAS). Clinical studies have shown that RAS activation may lead to hypertension, a major cardiovascular and renal risk factor. To delineate the underlying mechanisms of hypertension-induced nephropathy, we generated transgenic mice that overexpress rat ANG (rANG) in the kidney to establish whether intrarenal RAS activation alone can evoke hypertension and kidney damage and whether RAS blockade can reverse these effects. Transgenic mice overexpressing renal rANG were generated by employing the kidney-specific, androgen-regulated protein promoter linked to rANG cDNA. This promoter targets rANG cDNA to renal proximal tubules and responds to androgen stimulation. Transgenic mice displayed kidney-specific expression of rANG, significantly increased blood pressure (BP) and albuminuria in comparison to non-transgenic littermates. Administration of losartan (an angiotensin II (type 1)-receptor antagonist) or perindopril (an angiotensin-converting enzyme inhibitor) reversed these abnormalities in transgenic animals. Renal injury was evident on examination of the kidneys in transgenic mice, and attenuated by losartan and perindopril treatment. We conclude that the overproduction of ANG alone in the kidney induces an increase in systemic BP, proteinuria, and renal injury. RAS blockers prevent these abnormalities. These data support the role of the intrarenal RAS in the development of hypertension and renal injury.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Blotting, Western; DNA, Complementary; Female; Gene Expression Regulation; Hypertension; Immunohistochemistry; Kidney; Kidney Diseases; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Perindopril; Proteins; Proteinuria; Rats; Renin-Angiotensin System

Long-acting third-generation dihydropyridine calcium channel blockers (CCBs) improve endothelial dysfunction and prevent cardiovascular events in humans, but their cellular and molecular mechanisms of tissue protection are not elucidated in detail. We assessed organ (renal) protection by the highly lipophilic CCB lercanidipine in a double-transgenic rat (dTGR) model with overexpression of human renin and angiotensinogen genes. We randomly treated dTGR with lercanidipine (2.5 mg/kg/day; n=20) or vehicle (n=20) for 3 wk. Furthermore, we explored the influence of lercanidipine on protein kinase C (PKC) signaling in vivo and in vitro using endothelial and vascular smooth muscle cell cultures. Cumulative mortality was 60% in untreated dTGR, whereas none of the lercanidipine-treated animals died (P<0.001). We found significantly less albuminuria and improved renal function in lercanidipine-treated dTGR (both P<0.05). Lercanidipine treatment also significantly (P<0.05) reduced blood levels of the endogenous NOS inhibitor asymmetric dimethylarginine. On histological examination, we observed significantly less tissue inflammation and fibrosis in lercanidipine-treated animals (both P<0.05). Lercanidipine significantly inhibited angiotensin (ANG) I-mediated PKC-alpha and -delta activation in vivo and in vitro, partly due to reduced intracellular calcium flux. As a result, lercanidipine improved endothelial cell permeability in vitro. Lercanidipine prevents tissue injury and improves survival in a model of progressive organ damage. These effects may result, at least in part, from inhibition of tissue inflammation as well as improved NO bioavailability. Modulation of PKC activity may be an important underlying intracellular mechanism.

Topics: Albumins; Amidohydrolases; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Arginine; Calcium Channel Blockers; Dihydropyridines; Gene Expression Regulation, Enzymologic; Hypertension; Kidney; Rats; Rats, Sprague-Dawley; Renin

The objective of the present study was to determine whether angiotensinogen G(-6)A polymorphism is associated with the elevation of blood pressure (BP) in the hypertensive disorders of pregnancy in Korean population. The subjects included 201 cases with the hypertensive disorders of pregnancy and 160 healthy controls. The medical records of subjects were reviewed. Cases were classified into the four subtypes (transient hypertension, preeclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension) by the diagnostic criteria suggested by the National High Blood Pressure Education Program Working Group. Cases were also divided into the high and low BP group by the elevation of BP (diastolic BP greater than or equal to 110 mmHg). Maternal angiotensinogen G(-6)A polymorphism was determined by restriction fragment length polymorphism. Frequencies of AA genotype were significantly higher in the high than in the low BP group in the preeclampsia, superimposed preeclampsia, and the combined group (N = 201), suggesting that the angiotensinogen G(-6)A allele was significantly associated with the elevation of BP in the hypertensive disorders of pregnancy among South Korean women. The present findings imply that the elevation of BP can serve as an endophenotype for a spectrum of hypertensive conditions in pregnancy.

Topics: Analysis of Variance; Angiotensinogen; Case-Control Studies; Female; Genotype; Humans; Hypertension; Korea; Logistic Models; Phenotype; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular

Polymorphism of the gene encoding components of the renin-angiotensin-aldosterone synthase system (RAAS) represents an area of intense research of cardiovascular disease associations. Numerous studies have addressed the role of RAAS gene polymorphisms in the development and progression of renal disease. Also, it has been reported that patient with ACE (DD) and angiotensinogen AGT (TT) genotypes are associated with chronic allograft dysfunction (CAD). We investigated the effects of gene polymorphisms of the renin-angiotensin-aldosterone system in renal transplant patients (81 males and 50 females; mean age 29.6+/-10.2 years). Genotypes were determined using polymerase chain reaction sequence specific primers and PCR followed by RFLP analysis. Renal allograft recipients with chronic allograft dysfunction had significantly higher frequencies of the MM genotype than those without CAD (P<0.05). The other genetic polymorphisms of the RAAS were not associated with CAD. This study proves that determination of AGT M235T genotype before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.

Topics: Adult; Angiotensinogen; Cytochrome P-450 CYP11B2; Female; Graft Survival; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Transplantation, Homologous

Recent findings related to the renin-angiotensin system have provided a more elaborated understanding of the pathophysiology of hypertension and kidney diseases. These findings have led to unique concepts and issues regarding the intrarenal renin-angiotensin system. Angiotensinogen is the only known substrate for renin that is the rate-limiting enzyme of the renin-angiotensin system. Because the level of angiotensinogen in human beings is close to the Michaelis-Menten constant value for renin, changes in angiotensinogen levels can control the activity of the renin-angiotensin system, and its upregulation may lead to elevated angiotensin peptide levels and increases in blood pressure. Enhanced intrarenal angiotensinogen mRNA or protein levels or both have been observed in multiple models of hypertension including angiotensin II-dependent hypertensive rats, Dahl salt-sensitive hypertensive rats, and spontaneously hypertensive rats, as well as in kidney diseases including diabetic nephropathy, immunoglobulin A (IgA) nephropathy, and radiation nephropathy. Renal angiotensinogen is formed primarily in proximal tubular cells and is secreted into the tubular fluid. Urinary angiotensinogen excretion rates show a clear relationship to kidney angiotensin II contents and kidney angiotensinogen levels, suggesting that urinary angiotensinogen may serve as an index of the intrarenal renin-angiotensin system status. Establishment of concise and accurate methods to measure human angiotensinogen may allow clinical studies that would provide important information regarding the roles of intrarenal angiotensinogen in the development and progression of hypertension and kidney diseases.

Topics: Angiotensinogen; Animals; Biomarkers; Humans; Hypertension; Kidney Diseases; Kidney Tubules; Renin-Angiotensin System

Catecholaminergic and angiotensinergic systems are involved in the neural control of blood pressure. The present study analysed the expression of tyrosine hydroxylase (TH), a key enzyme for catecholamine synthesis and of angiotensinogen (AGT), the precursor of angiotensin II (Ang II), in areas of the central nervous system (CNS) involved with cardiovascular regulation such as nucleus tractus solitarius (NTS), ventrolateral medulla (VLM), locus coeruleus (LC) and hypothalamic paraventricular nucleus (PVN) 2 h, 3 and 7 days after aortic coarctated hypertensive rats. In situ hybridization, was employed for the analysis of messenger RNA (mRNA) expression with anatomical resolution. No changes were seen in TH and AGT mRNA expression in the analysed areas 2 h and 3 days after aortic coarctation when compared to the respective sham group. TH mRNA expression was increased in the NTS and LC of rats 7 days after coarctation hypertension when compared to sham rats. Time course analysis, showed an increase in TH mRNA expression in the NTS 7 days after aortic coarctation when compared to 2 h and 3 days groups, as well as an increase in LC 3 days and 7 days following coarctation hypertension in comparison with the 2 h group. Analysis of AGT mRNA in the NTS expression revealed a decrease at 3 days, followed by an increase in mRNA expression 7 days following coarctation hypertension when compared to the sham group. Time course analysis, showed an increase in AGT mRNA expression in the NTS 7 days after coarctation when compared to 2 h and 3 days groups. The results show that TH and AGT mRNA expression changes during the different phases of experimental hypertension, suggesting that the noradrenaline (NOR) and angiotensin II (Ang II) might participate in the modulation/maintenance of coarctation hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Aortic Coarctation; Blood Pressure; Brain; Brain Stem; Catecholamines; Disease Models, Animal; Gene Expression; Hypertension; Male; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred WKY; RNA, Messenger; Time Factors; Tyrosine 3-Monooxygenase; Up-Regulation

Renin-angiotensin System is essential for the homeostasis of blood pressure in humans. The roles of renin-angiotensin system gene polymorphisms including angiotensinogen, angiotensin-converting enzyme, renin and angiotensin II receptor, type 1 genes in the pathogenesis of preeclampsia have been extensively studied, but most association studies produced either negative or inconsistent results. Prolylcarboxypeptidase encodes a lysosomal enzyme and is a regulator for both renin-angiotensin system and the kallikrein-kinin system. There is no published study on prolylcarboxypeptidase gene and preeclampsia.. We investigated the independent and joint association of five polymorphisms in angiotensinogen, angiotensin-converting enzyme, and prolylcarboxypeptidase gene and chronic hypertension with the risk of preeclampsia in 125 preeclamptic and 1040 non-preeclamptic black women enrolled at the Boston Medical Center. We used logistic regression models to estimate the odds ratios of risk for preeclampsia associated with each gene polymorphism and its joint association with chronic hypertension.. No association was found in four polymorphisms in angiotensinogen and angiotensin-converting enzyme. Prolylcarboxypeptidase E112D (rs2298668) D allele along and jointly with chronic hypertension were associated with a significantly increased risk of preeclampsia. Compared to women with homozygous EE genotype and without chronic hypertension, higher risks of preeclampsia were observed in DD women without chronic hypertension (OR = 3.7, 95% CI, 1.2 - 12.4) and EE women with chronic hypertension (OR = 9.1, 95% CI: 4.7 - 17.6). Women with both D allele and chronic hypertension had the highest risk (OR = 158, 95% CI, 25-infinite). This finding was validated in an independent sample of 1,015 non-black women. We further compared the prolylcarboxypeptidase transcript levels in peripheral blood cells of 23 preeclamptic (30% with chronic hypertension) and 51 non-preeclamptic (6% with chronic hypertension) women 2 - 3 days after delivery. The PRCP transcript levels were lower in ED/DD women than in EE woman (P = .03) and lower in preeclamptic women than in non-preeclamptic women (P = .007).. Our data showed that prolylcarboxypeptidase D allele coupled with chronic hypertension was associated with a significantly increased risk of preeclampsia in both black and non-black women. Gene expression assays lent further support for the functional significance of prolylcarboxypeptidase in the etiology of preeclampsia.

Topics: Adult; Angiotensinogen; Black or African American; Boston; Carboxypeptidases; Case-Control Studies; Chronic Disease; Female; Gene Expression; Genotype; Humans; Hypertension; Odds Ratio; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Renin-Angiotensin System; White People

The mechanism of overproduction of aldosterone in primary aldosteronism is unclear. The intraadrenal renin-angiotensin system (RAS) has been suggested to possess the functional role of the synthesizing aldosterone and regulating blood pressure. In order to clarify the pathophysiological roles of adrenal RAS in aldosterone-producing adenoma (APA), we studied the expressions of the messenger RNAs (mRNAs) of renin, angiotensinogen, type 1 (AT1R) and type 2 angiotensin II receptor (AT2R), CYP11B1 (11 beta-hydroxylase gene) and CYP11B2 (aldosterone synthase gene) in 8 patients with angiotensin II-responsive (ATII-R) APA and compared them with the expressions of the same mRNAs in 8 patients with angiotensin II-unresponsive (ATII-U) APA. Quantification of the mRNA of each gene was done using a real-time polymerase chain reaction with specific primers. There were no significant differences between ATII-R APA and ATII-U APA in the mRNA levels of renin, angiotensinogen, AT1 R, CYP11B1 and CYP11B2. The amount of AT2R mRNA was significantly higher in the patients with ATII-R APA than in those with ATII-U APA (p<0.05). These results may suggest that AT2R partially contributes to the overproduction of aldosterone in ATII-R APA.

Topics: Adrenal Glands; Adult; Angiotensinogen; Blotting, Western; Cytochrome P-450 CYP11B2; Diuretics; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Steroid 11-beta-Hydroxylase

Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients. The aim of this study was investigate whether the alpha-adducin G460W polymorphism or angiotensinogen M235T polymorphism has an effect on the mean difference in blood pressure in subjects using antihypertensive drugs. Data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, was used. This study started in 1990 and included 7983 subjects of 55 years and older. Data from three examination rounds were used. Subjects were included when their blood pressure was elevated at 1 or more examinations and/or a diuretic, beta-blocker, calcium antagonist, or ACE inhibitor was used. A marginal generalized linear model was used to assess the drug-gene interaction. In total, 3025 hypertensives were included. No drug-gene interaction on blood pressure levels was found. The mean difference in systolic blood pressure (SBP) between subjects with the W-allele and GG genotype of the alpha-adducin gene was for diuretic users 1.25 mmHg (95% CI:-2.86 to 5.35), for beta-blockers 0.02 mmHg (95% CI:-3.39 to 3.42), for calcium antagonists -0.70 mmHg (95% CI:-5.61 to 4.21), and for ACE inhibitors -3.50 mmHg (95% CI:-9.02 to 2.02). The mean difference in SBP between subjects with the TT and MM genotype was for diuretic users -2.33 mmHg (95% CI:-8.32 to 3.66), for beta-blocker -0.06 mmHg (95% CI:-4.91 to 4.79), for calcium antagonist 0.59 mmHg (95% CI:-5.95 to 7.13), and for ACE inhibitor -2.33 mmHg (95% CI:-9.66 to 5.01). The G460W polymorphism and the M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Calcium Channel Blockers; Calmodulin-Binding Proteins; Cohort Studies; Diuretics; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Retrospective Studies

Conflicting results are to be found in the literature on the relationship between the M235T polymorphism of the angiotensinogen (AGT) gene and hypertension. The controversy may be due to insufficient numbers of subjects, the variability of the inclusion criteria and the different genotype analysis methods used. We have experienced that the most frequently used, original polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method involves significant uncertainties when the TT genotype is determined, independently of the restriction digestion. To make the determination more accurate, we improved the PCR by designing a new antisense primer containing only one mismatch instead of the two in the original protocol and also by adding DMSO to the PCR reaction mixture. The original and our improved methods were compared by using DNA from 123 patients: parallel determinations resulted in values of 33 MM, 90 MT and 0 TT with the original method and of 33 MM, 56 MT and 34 TT with the improved RFLP protocol. In summary, a plausible explanation for some of the conflicting data published on AGT M235T polymorphism may be that inaccuracies arose during the determination of the genotype.

Topics: Angiotensinogen; Gene Frequency; Genotype; Humans; Hypertension; Methionine; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Threonine

The objective of this study was to evaluate the impact of variations of the angiotensinogen (AGT) and angiotensin II type I receptor (AGTR1) genes on progression of blood pressure (BP) and left ventricular mass (LVM) in multiethnic youth. The study was longitudinal involving 581 European American (EA) and African American (AA) youth with 12 assessments over a 15-year period. AGT M235T and three AGTR1 polymorphisms (C-521T, L191L and A1166C) were genotyped and individual growth curve modeling analyses were conducted. Single nucleotide polymorphism (SNP) analyses found a significant 3-way interaction between M235T, ethnicity and gender on BP levels. Systolic BP (SBP) levels were 5.8 mmHg (p = .00003) and diastolic BP (DBP) levels were 2.6 mmHg (p = .005) lower in carriers versus noncarriers of the M235 allele in AA males only. Furthermore, the AGTR1 L191 allele showed a SBP lowering effect in subjects with a high socioeconomic status (SES;p = .048) and a DBP lowering effect in AAs (p = .038). Haplotype analyses identified a protective haplotype (C-521, 191L and A1166) for LVM levels (p = .03). LVM in individuals homozygous for this haplotype was 12.9 g lower than those homozygous for the most common haplotype (-521T, 191L and A1166). No significant interactions were found between the AGT M235T polymorphism and any of the single SNPs or haplotypes of the AGTR1 gene. Our results in multiethnic youth uncover an ethnicity and gender-specific effect of the AGT M235T polymorphism and a SES or ethnicity-specific effect of the AGTR1 L191L polymorphism on the progression of hypertension risk. A protective AGTR1 haplotype for LVM was also identified.

Topics: Adolescent; Alleles; Angiotensinogen; Black People; Blood Pressure; Child; Female; Gene Frequency; Genotype; Haplotypes; Humans; Hypertension; Hypertrophy, Left Ventricular; Longitudinal Studies; Male; Models, Statistical; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Sex Factors; Social Class; Ventricular Function, Left; White People

Cytokines are emerging as important in developmental processes. They may induce alterations in normal gene expression patterns, activate angiotensinogen transcription, or alter expression of the renin-angiotensin system (RAS). To determine whether prenatal exposure to interleukin-6 (IL-6) influences gene expression of the intrarenal RAS and contributes to renal dysfunction and hypertension in adulthood, we exposed female rats to IL-6 early (EIL-6 females) and late (LIL-6 females) in pregnancy and analysed blood pressure in the offspring at 5-20 weeks of age. Renal fluid and electrolyte excretion was assessed in clearance experiments, mRNA expression by real-time PCR, and protein levels by Western blot. Systolic pressure was increased at 5 weeks in IL-6 females and at 11 weeks in males. Circulatory RAS levels were increased in all IL-6 females, but angiotensin-1-converting enzyme (ACE) activity was increased only in LIL-6 females. LIL-6 males and IL-6 females showed decreased urinary flow rate and urinary sodium and potassium excretion. Dopamine excretion was decreased IL-6 females. In adult renal cortex, renin expression was increased in all IL-6 females, but angiotensinogen mRNA was increased only in LIL-6 females; AT(1) receptor (AT(1)-R) mRNA and protein levels were increased in LIL-6 females, whereas AT(2) receptor (AT(2)-R) levels were decreased in LIL-6 females and EIL-6 males. In adult renal medulla, AT(1)-R protein levels were increased in LIL-6 females, and AT(2)-R mRNA and protein levels were decreased in EIL-6 males and LIL-6 females. Prenatal IL-6 exposure may cause hypertension by altering the renal and circulatory RAS and renal fluid and electrolyte excretion, especially in females.

Topics: Angiotensinogen; Animals; Blood Pressure; Dopamine; Female; Gene Expression Regulation; Hypertension; Interleukin-6; Kidney; Male; Peptidyl-Dipeptidase A; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; RNA, Messenger; Sex Factors; Sodium; Time Factors; Urodynamics

To determine whether angiotensin-converting enzyme (ACE) and angiotensinogen (ACT) genotypes could predict changes in urinary sodium excretion in response to short-term aerobic exercise training (AEX).. Longitudinal intervention.. The study was conducted at the University of Maryland at College Park and at Baltimore, and the University of Pittsburgh General Clinical Research Center.. 31 (age 53 +/- 2 years) sedentary, hypertensive (146 +/- 2/88 +/- 2 mm Hg) African Americans.. Aerobic exercise training (AEX) consisted of seven or eight consecutive days, 50 minutes per day, at 65% of heart rate reserve. Participants underwent a 24-hour period of ambulatory blood pressure (BP) monitoring and urine collection at baseline and 14-18 hours after the last exercise session.. Angiotensiongen (AGT) M235T and ACE I/D genotype and sodium excretion and ambulatory BP.. Average sodium excretion for the entire group independent of genotype increased after AEX (108 +/- 9 vs 143 +/- 12 mEq/day, P=.003). Sodium excretion significantly increased after exercise training in the ACE II (114 +/- 22 vs 169 +/- 39 mEq/day, P=.04), but not in the ID (100 +/- 8 vs 133 +/- 17 mEq/day, P=.12) or DD (113 +/- 18 vs 138 +/- 11 mEq/day, P=.13) genotype groups. In the II genotype group, the increase in sodium excretion was significantly and inversely correlated with decreases in 24-hour diastolic (r= -.88, P=.02) and mean (r= -.95, P=.004) BP. The ACT TT and MT+MM genotype groups similarly increased their sodium excretion by 34 +/- 16 (P=.05) and 37 +/- 17 (P=.05) mEq/day respectively.. These results suggest that African American hypertensives with the ACE II genotype may be more susceptible to sodium balance and BP changes with exercise training compared with those with the ID and DD genotypes.

Topics: Angiotensinogen; Black or African American; Exercise; Female; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Sodium

Topics: Angiotensinogen; Cardiovascular Diseases; Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Genetic; Racial Groups

The M235T mutation of the human angiotensinogen gene has been shown to be associated with elevated circulating angiotensinogen concentrations and essential hypertension. The frequencies of the 235T allele are significantly different in black and white subjects. We analyzed the independent contribution of the angiotensinogen M235T mutation to the development of recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) in a cohort of 916 black (n=145) and white (n=771) postmyocardial infarction patients who were prospectively studied during an average follow-up of 28 months. The frequency of the 235T allele was significantly higher among black (82%) than among white (44%) patients (P<0.001). There was no evidence for Hardy-Weinberg disequilibrium. During follow-up, 41 cardiac events (28%) occurred in blacks and 197 (26%) in whites (P=0.49). Multivariate Cox proportional hazards regression analysis demonstrated that 235T homozygosity was independently associated with increased risk of coronary events among black (hazard ratio: 2.37; P=0.04) but not white (hazard ratio: 0.93; P=0.68) patients, with a significant ethnic-related interaction effect (P for the difference=0.04). Among hypertensive black patients, the TT genotype was associated with a 3.3-fold (P=0.02) increase in the risk of coronary events. Our findings suggest that homozygosity for the 235T mutation in the angiotensinogen gene is an independent risk factor for coronary events in black postmyocardial infarction patients. The presence of hypertension significantly augments the risk associated with this genetic mutation.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Black People; Cardiovascular Diseases; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Homozygote; Humans; Hypertension; Male; Methionine; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Prospective Studies; Recurrence; Threonine; White People

Molecular variants of angiotensinogen (AGT) have been associated with AGT level and hypertension (HT). However, results from reported studies vary considerably between- and within-studied populations. We performed association analysis of AGT gene variants with AGT levels and HT in samples of African descent families, including 595 Nigerians and 901 African Americans. We evaluated association using haplotypes defined by a set of single-nucleotide polymorphisms selected from a previous detailed study of the gene haplotype structure. In the sample of Nigerian families, AGT haplotype H1 was associated with high plasma level. Results were not significant for blood pressure (BP) or HT. For the African-American population, we found significant association between low plasma AGT level and haplotype H7. Furthermore, we found weak associations of H1 with hypertensive status and H7 with low systolic BP. However, no significant association between H1 and high plasma level was found. We conclude that the two distantly related haplotypes, H1 and H7, are associated, but have opposite effects on the phenotypes in two populations of African origin.

Topics: Adult; Angiotensinogen; Biomarkers; Black or African American; Black People; Blood Pressure; Body Mass Index; Chicago; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Nigeria; Polymorphism, Single Nucleotide; Predictive Value of Tests

Essential hypertension is a complex multifactorial disease caused by ill-defined genetic factors. The angiotensinogen (AGT) gene has been implicated as a risk factor in essential hypertension.. To assess the role of AGT in hypertension, we evaluated two polymorphisms (A-6G and C-20A) in the 5' region of the gene that have been shown to have a role in transcriptional regulation. A total of 463 subjects were studied: 243 African Americans (26 male and 34 female normotensives, 66 male and 117 female hypertensives) and 220 whites (35 male and 60 female normotensives, 55 male and 70 female hypertensives). African American and white subjects were examined individually, as significant differences in allele and genotype frequencies were observed between these two cohorts.. White female hypertensives and normotensives differed significantly in genotype frequency at C-20A (P = .02). No other single site comparisons were significantly different between hypertensives and normotensives in either the white or African American samples. Haplotype frequencies in white males also differed significantly between phenotypic classes (P = .05). To evaluate the data further, we assessed all polymorphic sites simultaneously by the examination of multisite interaction and determined the single best genetic model for each population. A model that included both sites and gender correctly predicted hypertension status in the white population 59.1% of the time (P = .039). The model generated for the African American population was not significant.. Our results suggest that a complex set of genetic factors interact with gender to predispose whites to hypertension.

Topics: Adenine; Angiotensinogen; Black or African American; Cohort Studies; Cytosine; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Models, Genetic; New York; Polymorphism, Single Nucleotide; Predictive Value of Tests; Promoter Regions, Genetic; Reproducibility of Results; Risk Factors; Sex Characteristics; Sex Distribution; Sex Factors; White People

Angiotensinogen (AGT) gene has been regarded as one of the candidate genes for essential hypertension. In our study, the role of AGT gene as a putatively predisposing gene for hypertension was evaluated by genotyping a A (-6) G polymorphism in the core promoter region in 123 patients with essential hypertension and 103 healthy controls. A microchip electrophoresis method coupled with polymorphism chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay was used for genotyping the A (-6) G single-nucleotide polymorphism. The separation and detection of the digested PCR amplicons were completed just in 280 s or less. The genotype frequency fulfilled the criteria of the Hardy-Weinbery equilibrium (X2 = 3.067, P > 0.05). The results showed a higher frequency of the -6 A allele (0.70) in the normotensive subjects, which is higher than those reported in Germany (0.47) and Czech (0.40) populations, but similar to that found in Japanese populations (0.73). The frequencies of genotype AA, AG, and GG were 0.46, 0.49, and 0.05 in hypertensive subjects, and 0.44, 0.53, and 0.03 in control subjects. There is no significant difference in the distributions of the genotype and allele between the two groups (X2 = 0.88, P > 0.05; X2 = 0.024, P > 0.05). These findings differ from some of the results obtained in other ethnic groups, indicating the potential importance of ethnic origin in the assessment of genetic risk identifiers for a complex disease.

Topics: Aged; Angiotensinogen; China; Electrophoresis, Microchip; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Hypertension is a serious health problem particularly for African-Americans. Previous studies have suggested that angiotensinogen (AGT) gene locus is involved in human essential hypertension. We have recently shown that an A/G polymorphism at -217 in the promoter of the AGT gene is associated with essential hypertension especially in African-Americans. We report here that A/G polymorphism at -217 affects the glucocorticoid-induced promoter activity of the human AGT gene. We show that recombinant glucocorticoid receptor (GR) binds strongly to the AGT gene promoter when nucleoside A is present at -217, and dexamethasone treatment increases the interleukin 6 induced promoter activity of reporter constructs containing nucleoside A at -217. Similarly cotransfection of GR and C/EBP beta or C/EBP delta increases the promoter activity of reporter construct containing nucleoside A at -217. Since AGT is an acute phase protein, we propose that increased expression of -217A allele of the AGT gene by glucocorticoids and C/EBP family of transcription factors may be involved in essential hypertension.

Topics: Angiotensinogen; Carcinoma, Hepatocellular; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Protein-delta; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; Dexamethasone; DNA Primers; Gene Expression Regulation; Glucocorticoids; Humans; Hypertension; Interleukin-6; Kidney; Liver Neoplasms; Mutation; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Glucocorticoid; Recombinant Proteins; Regulatory Sequences, Nucleic Acid; Transcription Factors; Transcription, Genetic; Transfection

Essential hypertension is a major public health concern worldwide where its prevalence accounts for various cerebrovascular diseases. A common molecular variant of angiotensinogen (AGT), the precursor of potent vasoactive hormone angiotensin II, has been incriminated as a marker for genetic predisposition to essential hypertension in some ethnics. This case-control study was designed not only to determine the association of the AGT M235T gene variants with essential hypertension, but also its relationship to Plasma Renin Activity (PRA) in subjects attending the Health Clinic, Kuala Lumpur, Malaysia.. The study involved 188 subjects, 101 hypertensives and 87 normotensives. Consents were obtained from all the participated subjects. M235T gene variants were investigated using allele specific polymerase chain reaction and PRA was determined by radioimmunoassay. Hypertensinogenic factors such as dietary habits, physical activity, smoking and drinking habits were assessed using a pre-tested questionnaire.. The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (chi2 = 23.184, P < 0.001 and chi2 = 21.482, P < 0.001, respectively). The odds ratio for hypertension was 1.36 (95% confidence interval 1.03-1.80) for subjects with homozygous mutated allele TT of the M235T variant compared with other genotypes or 1.98 (95% confidence interval 1.46-2.67) for those carrying T allele compared to those carrying M allele. Plasma Renin Activity is also significantly higher in hypertensive subjects (PRA = 3.8 +/- 2.5 ngAI/ml/hr for hypertensives, PRA = 2.6 +/- 1.3 ngAI/ml/hr for normotensives, P < 0.001), but was not significantly different between groups of genotypes (P = 0.118).. The M235T variant of the AGT is significantly associated with essential hypertension whereas the genotype TT or allele T is a possible genetic marker or risk factor for hypertension in Malaysian subjects.

Topics: Adult; Aged; Analysis of Variance; Angiotensinogen; Blood Pressure; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Malaysia; Male; Middle Aged; Mutation; Polymorphism, Genetic; Regression Analysis; Renin

This study was performed to determine whether augmented intrarenal angiotensinogen may contribute to the enhanced renal angiotensin II (Ang II) and associated tissue injury in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were maintained on a normal diet and killed at either 7 or 14 wk of age. Two groups of SHR received either an Ang II type 1 receptor blocker (ARB; olmesartan, 5 mg/d) or a triple therapy (hydralazine 7.5 mg/d, reserpine 0.15 mg/d, and hydrochlorothiazide 3 mg/d [HRH]) during weeks 7 through 14. Systolic BP and renal Ang II were significantly increased in SHR-14 (n = 8) compared with WKY-7, WKY-14, and SHR-7 (n = 8 each), and ARB treatment prevented these increases (n = 8). However, whereas HRH treatment prevented the development of hypertension in SHR, this combination therapy failed to decrease renal Ang II (n = 8). With the use of urine samples or fixed renal sections, renal injuries in rats were quantified in a semiautomated manner by the following six parameters: (1) urinary excretion rate of total protein, (2) glomerular sclerosis, (3) interstitial expansion, (4) and (5) numbers of monocytes/macrophages in interstitium or glomeruli, and (6) arterial proliferation. Angiotensinogen mRNA and protein levels in kidney cortex, measured by real-time reverse transcriptase-PCR and Western blot analysis, respectively, and all six parameters of renal damage were changed in parallel, and ARB treatment also prevented these increases. However, HRH treatment failed to prevent these increases. These results indicate that SHR have enhanced intrarenal angiotensinogen production that contributes to increased Ang II levels leading to the development of hypertension and renal injury in this strain.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Hypertension; Kidney Diseases; Male; Rats; Rats, Inbred SHR

Hypertension is the most common risk factor for hemorrhagic stroke. An experimental model of stroke, the stroke-prone spontaneously hypertensive rat (SHRSP), which has been enormously useful in studies of cerebral circulation, has been used in >1000 papers. However, SHRSP usually have an ischemic or less commonly hemorrhagic stroke in the cortex, not in the brain stem, cerebellum, or basal ganglia, as in patients with hypertension. The goal of this study was to develop a model of hemorrhagic stroke in hypertensive mice.. A genetic model of hypertensive mice, double transgenic mice (R+/A+) that overexpress both human renin (R+) and human angiotensinogen (A+), and nonhypertensive control mice were divided into 3 groups: (1) high-salt diet; (2) Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthases, in drinking water; and (3) high-salt diet and L-NAME.. All R+/A+ mice on high-salt diet and L-NAME died within 10 weeks, with hemorrhage in the brain stem, and several of the mice had hemorrhages in brain stem, cerebellum, and basal ganglia. No control mice on high-salt diet and L-NAME had hemorrhagic stroke. Arterial pressure in R+/A+ mice increased progressively during high-salt diet and L-NAME. In R+/A+ and control mice, high-salt diet or L-NAME alone did not increase arterial pressure.. We now describe the first model of spontaneous hemorrhagic strokes in hypertensive mice. The type and locations of stroke are reasonably similar to those observed in patients with hypertension.

Topics: Angiotensinogen; Animal Feed; Animals; Blood Pressure; Brain; Circadian Rhythm; Disease Models, Animal; Female; Humans; Hypertension; Intracranial Hemorrhages; Mice; Mice, Transgenic; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Renin; Salts; Stroke

Blood pressure-independent (BP) effects of angiotensin (Ang) II and endothelin (ET) on coronaries (remodeling) in high renin hypertension are incompletely understood.. We studied the effects of subdepressor doses of Ang II receptor (AT1) blockade with losartan (10 mg/kg/day gavage) and endothelin A receptor (ETA) blockade with LU135252 (30 mg/kg/day) on the coronaries of rats harboring human renin and angiotensinogen genes (dTGR). Nontransgenic Sprague-Dawley rats were controls. The rats were treated between the ages of 6 and 10 weeks. Coronary cross-sectional area [CSA; 0.79 x (external diameter2 - internal diameter2)], cell proliferation, and infiltration of monocytes/macrophages were determined.. Monotherapy did not lower BP while combination treatment did (p < 0.05). All treatments reduced mortality (p < 0.01). CSA was decreased by all treatments compared to vehicle, independent of blood pressure (p < 0.05). Extensive proliferation by PCNA staining and infiltration of ED-1-positive cells was diminished by both treatment and the combination.. The data show that Ang II promotes coronary inflammation and remodeling, in part independent of blood pressure but dependent upon ET signaling. Combination treatment directed at both pathways may improve outcome, independent of blood pressure reduction.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Aorta; Blood Pressure; Cell Movement; Cell Proliferation; Coronary Vessels; Disease Models, Animal; Endothelin A Receptor Antagonists; Humans; Hypertension; Macrophages; Male; Rats; Rats, Sprague-Dawley; Renin

Genetic polymorphisms of the renin-angiotensin system (RAS) has been associated with cardiovascular events and the progression of nephropathy in several diseases. The objective of this study was to evaluate a possible association of the genetic polymorphisms of RAS with the development and/or progression of lupus nephritis in a Brazilian population. Seventy-five SLE patients with lupus nephropathy (LN group) were compared to 72 SLE patients without LN (SLE group) and 65 healthy individuals (CONTROL group), of sex and ethnic matched, in a Brazilian population sample. Mean global follow-up was 9 +/- 6 years for lupus without nephropathy and 11 +/- 7 years for lupus nephropathy. Following the extraction of genomic DNA from the leukocytes in the peripheral blood, angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT M(235)T) and angiotensin II type 1 receptor (AGTR1 A(1166)C) genotypes were determined by the polymerase chain reaction. No significant difference of ACE, AGT and AGTR1 genotypes distribution between groups was observed in this study. There was no significant association between the variables of the RAS genotypes and the presence of hypertension in SLE. However, an increased frequency ofDD genotype (ACE I/D) was observed in SLE patients with LN who progressed to CRF compared to healthy controls (DD 60%, DI 26.7%, II 13.3% versus 27.7%, 60% and 12.3%, respectively; chi2 = 6.299, P = 0.0429). In the population studied, there was no influence of the RAS genetic polymorphisms in the development of lupus nephropathy, but the progression to CRF was associated with ACE DD polymorphism.

Topics: Adult; Angiotensinogen; Brazil; Case-Control Studies; Disease Progression; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The efficiency of magnetic laser therapy was evaluated in patients with essential hypertension (stages I and II). The role of angiotensinogen, angiotensin-converting enzyme, type II bradykinin receptor, and endothelial nitrogen oxide synthetase gene polymorphism in the realization of hypotensive effect of magnetic laser therapy was evaluated. The hypotensive effect of magnetic laser therapy depends on the polymorphism of the studied genes and is maximum in patients with MM polymorphism of angiotensinogen gene and DD polymorphism of angiotensin-converting enzyme gene. Additive interaction between angiotensin-converting enzyme and angiotensinogen genes in the formation of hemodynamic effects of magnetic laser therapy was detected.

Topics: Angiotensinogen; Humans; Hypertension; Low-Level Light Therapy; Magnetics; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Bradykinin B2

Despite excellent antihypertensive drugs on the market, about 70% of all hypertensive patients do not have their blood pressure under control. This is due to problems of compliance, largely because of having to take drugs daily and side effects. We propose an antisense therapy for hypertension because antisense treatment can provide long-lasting, highly specific control of blood pressure. Antisense to oligonucleotides can be designed to inhibit genes that produce proteins known to be overactive in hypertension and that are proven targets of current drug treatments. These include beta1-receptors, angiotensin-converting enzyme (ACE), and angiotensin type 1 receptors (AT1R). Antisense oligonucleotides are short (12-20 bases), single strands of DNA. They are designed to hybridize to specific mRNA and prevent translation of the target protein. Antisense inhibition of ACE, angiotensinogen or AT1R genes components of the renin-angiotensin system effectively reduce high blood pressure in animal models of hypertension. These include a genetic model (SHR) a surgical model (2KIC), and an environmental model (cold-induced hypertension). In all models, a single systemic administration of antisense decreased blood pressure by about 25 mmHg, and the effect could last up to 1 mo. No toxic effects of repeated antisense treatment were found. The results indicate that antisense therapy could be used for human hypertension and provide long-term protection that would increase compliance of patients.

Topics: Angiotensin Receptor Antagonists; Angiotensinogen; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Oligonucleotides, Antisense; Peptidyl-Dipeptidase A; Plasmids; Receptors, Angiotensin; Renin-Angiotensin System; Viruses

To assess the association between the egogram and hypertension in pregnancy (HP), a case-control study was carried out. Seventy-one HP cases, primiparous aged 20 to 34 years, and 109 controls, were enrolled among pregnant women who visited our hospitals for obstetrical care. Data from a self-administered questionnaire containing a Self Grow-Up Egogram (SGE) were subjected to univariate and multivariate analyses with prepregnancy body mass index (BMI) and angiotensinogen (AGT) genotype. The mean +/- standard error of total scores for the critical parent (CP) scale were 9.7 +/- 0.5 for cases and 8.3 +/- 0.3 for controls, those for the nurturing parent (NP) scale were 13.6 +/- 0.4 for cases and 13.4 +/- 0.3 for controls, those for the adult (A) scale were 11.3 +/- 0.5 for cases and 10.9 +/- 0.3 for controls, those for the free child (FC) scale were 12.3 +/- 0.3 for cases and 13.8 +/- 0.3 for controls, and those for the adapted child (AC) scale were 10.2 +/- 0.4 for cases and 8.5 +/- 0.4 for controls. A low FC scale score (FC < or = 10) and a high AC scale score (AC > 10) were significantly associated with HP ( p < 0.05; p < 0.01, respectively). In the multivariate analysis, FC < or = 10, AC > 10, prepregnancy BMI > or = 24, and homozygosity of the T235 allele genotype of the AGT gene were detected as the potent independent risk factors for HP. The odds ratios were 2.2, 2.8, 4.0, and 2.5, respectively. The present results suggest that a low FC score and a high AC score may be potent, independent risk factors for HP.

Topics: Adult; Analysis of Variance; Angiotensinogen; Body Mass Index; Case-Control Studies; Ego; Female; Genotype; Humans; Hypertension; Odds Ratio; Parent-Child Relations; Personality Assessment; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; Surveys and Questionnaires

We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202+/-4 mm Hg), serum creatinine, and albuminuria (34+/-5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115+/-6 and 139+/-5 mm Hg) and albuminuria (0.4+/-0.1 and 1.6+/-0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148+/-4 mm Hg) and albuminuria (2.1+/-0.7 mg per day), low-dose Val reduced BP (182+/-3 mm Hg) and albuminuria (24+/-3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4+/-0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and beta-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Echocardiography; Fumarates; Humans; Hypertension; Kidney; Rats; Rats, Sprague-Dawley; Renin; Tetrazoles; Valine; Valsartan

Silent white matter lesions (WMLs) may represent early target organ damage of the brain in patients with hypertension. Because these lesions may have a genetic background, we assessed the associations between polymorphisms of the renin-angiotensin system and the endothelial NO synthase (NOS3) genes and silent WMLs.. Ninety-three hypertensive individuals were studied. MRI of the brain was performed to obtain estimates of the total volume of subcortical and the extent of periventricular WMLs. Patients were genotyped for the angiotensinogen (M235T), the angiotensin-converting enzyme (insertion/deletion [I/D]), the angiotensin II type 1 receptor (AGTR1 A1166C), and the NOS3 (G894T) genes. A linear regression model was used to assess the relationship of these gene polymorphisms with both subtypes of WMLs.. When adjusted for age, diabetes mellitus, and blood pressure, subcortical WML volume was lowest in the presence of 1 or 2 AGTR1 C alleles (unstandardized beta, -38.8 [95% CI, -66.1 to -11.4] and -112.6 [CI, -188.9 to -36.4], respectively), whereas it was highest in the presence of an NOS3 T allele (31.1[corrected] [CI, 3.6 to 58.4]). No interaction between these polymorphisms on WMLs could be demonstrated. No associations were present with the other polymorphisms, either with subcortical or periventricular lesions.. We found the AGTR1 A1166C as well as the NOS3 G894T polymorphisms to be associated with silent WMLs in the subcortical area.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Angiotensinogen; Blood Pressure; Brain; Brain Injuries; Diabetes Mellitus; Female; Gene Frequency; Genotype; Humans; Hypertension; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Regression Analysis; Risk Factors

Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue characterized by extracellular matrix alterations with elastin fragmentation and excessive proteoglycan deposition. Xylosyltransferase I (XT-I, E.C. 2.4.2.26) is the initial enzyme in the biosynthesis of the glycosaminoglycan chains in proteoglycans and has been shown to be a marker of tissue remodeling processes. Here, we investigated for the first time serum XT-I activities in a large cohort of German PXE patients and their unaffected relatives. XT-I activities were measured in serum samples from 113 Caucasian patients with PXE and 103 unaffected first-degree family members. The occurrence of the frequent ABCC6 gene mutation c.3421C>T (R1141X) and the hypertension-associated genetic variants T174M and M235T in the angiotensinogen (AGT) gene were determined. Serum XT-I activities in male and female PXE patients were significantly increased compared to unaffected family members (male patients, mean value 0.96 mU/l, SD 0.37; male relatives, 0.78 mU/l, SD 0.29; female patients, 0.91 mU/l, SD 0.31; female relatives, 0.76 mU/l, SD 0.34; p<0.05). The mean XT-I activities in PXE patients with hypertension were 24% higher than in patients without increased blood pressure (p<0.05). The AGT T174M and M235T frequencies were not different in hypertensive PXE patients, normotensive PXE patients, family members or blood donors. Our data show that the altered proteoglycan biosynthesis in PXE patients is closely related to an increased XT-I activity in blood. Serum XT-I, the novel fibrosis marker, may be useful for the assessment of extracellular matrix alterations and disease activity in PXE.

Topics: Adult; Angiotensinogen; Case-Control Studies; Cohort Studies; DNA Mutational Analysis; Female; Genes, Recessive; Genetic Markers; Genetic Variation; Germany; Heterozygote; Humans; Hypertension; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Mutation; Pentosyltransferases; Polymorphism, Restriction Fragment Length; Proteoglycans; Pseudoxanthoma Elasticum; UDP Xylose-Protein Xylosyltransferase; White People

Molecular variants of angiotensinogen (AGT) have been linked to essential hypertension, and promoter variants have been shown to alter the transcription rate of AGT in vitro. We employed a case-control study to determine whether single nucleotide polymorphisms (SNPs) in the promoter region of AGT were associated with hypertension in African-Americans and Caucasians.. The frequencies of the variants at base positions -6, -20, -217, -793, and -776, both alone and in combination (haplotypes), were compared between cases and controls in samples stratified based on race and sex. A logistic regression model was applied to test whether AGT genotypes were significant predictors of the disease while adjusting for race, sex, and age.. Subjects with the AA or AG genotype at locus -793 were significantly more likely to have the disease (OR = 1.88, 95% CI = 1.12-3.15). Additionally, the differences in haplotype frequency distributions between cases and controls were significant at the 7% level for all four subgroups (stratified by race and sex) after adjusting for multiple testing. Based on the odds ratios for each individual haplotype, the haplotype AAAAT (nucleotide sequences at base positions -6, -20, -217, -793, -776) in African-American males, African-American females, and Caucasian females may confer susceptibility to the disease in these population subsets.. Overall, the present report provides statistical evidence for the association of AGT with essential hypertension.

Topics: Aged; Angiotensinogen; Black or African American; Case-Control Studies; Female; Gene Frequency; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; White People

To investigate the association between M235T variant of angiotensinogen (AGT) gene and the blood pressure response to benazepril in a hypertensive cohort.. Benazepril (10-20 mg/day) was administered for 6 weeks to 251 essential hypertensives. Polymerase chain reaction (PCR) combined with restriction enzyme digestion was used to detect the polymorphism and the patients were classified as MM, MT or TT genotype. The changes in systolic and diastolic blood pressure (SBP and DBP) were analyzed for association with genotypes at the AGT gene locus.. The MM genotype was observed in 23 patients (9.2%), the MT genotype in 104 patients (41.4%) and the TT genotype in 124 patients (49.4%). There was no association between these polymorphisms and the blood pressure responses in the total 251 patients. But based on the analysis stratified by age, the association between these polymorphism and the DBP responses was found in the old patients (> or = 60 years old) subgroup, the reduction in DBP was significantly greater in patients carrying the MM compared to MT or TT genotypes (14.8 +/- 4.8 mm Hg vs. 7.9 +/- 7.7 mm Hg or 9.8 +/- 6.4 mm Hg respectively; ANOVA, P = 0.034).. The M235T polymorphism of the AGT gene was shown to influence the responses to benazepril in old hypertensive patients (> or = 60 years old). Thus, specific genotypes might predict the response to specific antihypertensive treatment.

Topics: Aged; Angiotensinogen; Antihypertensive Agents; Benzazepines; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide

Several studies have shown an association between single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene and hypertension. Because hypertension is a risk factor for left ventricular (LV) hypertrophy and because evidence from animal models suggests that AGT may play a role in the growth and hypertrophy of the heart, we chose to conduct a population association study examining the relationship of 10 SNPs in the AGT gene with 7 different LV phenotypes measured by echocardiography. Participants (336 whites and 441 blacks) were drawn from the Hypertension Genetic Epidemiology Network (HyperGEN) study. Individuals were genotyped for 10 previously identified SNPs within the AGT gene. SNP genotype results were regressed against continuous LV phenotypes to test associations separately in each race. Using a cutoff of P<0.005 to account for multiple testing, we found 1 SNP (rs943580) significantly associated with transmitral early peak filling velocity (MVE) in the black population. We also used Phase 2.0.2 to reconstruct haplotypes from genotype data. Using the same cutoff of P<0.005, we found no haplotypes to be significantly associated with the LV phenotypes. To better understand the association between rs943580 and MVE, we examined AGT haplotype associations with MVE. The single SNP association was driven by a large group of SNPs in high linkage disequilibrium that includes the promoter SNP rs5051.

Topics: Aged; Angiotensinogen; Blood Flow Velocity; Echocardiography; Female; Genotype; Haplotypes; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Mitral Valve; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide

Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity.. A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes.. In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites.. Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Topics: Analysis of Variance; Angiotensinogen; Black or African American; Blood Pressure; Body Mass Index; Cluster Analysis; Female; Genetic Variation; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Regulatory Sequences, Nucleic Acid; White People

We examined the interactions between lifestyle and polymorphisms of salt-sensitive genes and their effects on hypertension in a general Japanese sample (The Shigaraki Study). The study group consisted of 2,902 subjects who underwent a medical examination in 1999 in Shigaraki, a suburban area in Shiga. Among 1,647 subjects not receiving antihypertensive medication, in a combined analysis of angiotensinogen (AGT) and adducin (ADD1) polymorphisms, double homozygosity of 235Thr or 460Trp was not found to be associated with hypertension. A multiple logistic regression analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [95% CI]: 1.06-1.08), body mass index (BMI) (OR: 1.18, 95% CI: 1.13-1.23), alcohol consumption (OR: 1.39, 95% CI: 1.16-1.66), family history of hypertension (OR: 1.57, 95% CI: 1.18-2.07), and combined AGT M235T Thr/Thr and ADD1 Trp/Trp polymorphisms (OR: 1.37, 95% CI: 1.03-1.82) were associated with hypertension. However, there was no interaction between eating salty food and combined AGT and ADD1 polymorphisms. Furthermore, eating salty food was not associated with hypertension in a multivariate analysis. Therefore, a combination of the AGT and ADD1 polymorphisms appears to be associated with hypertension. However, a simple questionnaire regarding salt intake was not sufficient to confirm the relationship between salt intake and hypertension and/or salt-sensitive genes.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Calmodulin-Binding Proteins; Female; Genotype; Homozygote; Humans; Hypertension; Japan; Life Style; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Polymorphism, Genetic; Regression Analysis; Sodium Chloride, Dietary; Surveys and Questionnaires

Numerous association studies have been performed to evaluate the relationship between the angiotensinogen gene and the essential hypertension, but their results are conflicting. The conflicting results may be explained by methodological reasons, particularly genetic differences in the population samples, phenotypic differences in the hypertensive populations analyzed, lack of appropriate control for other hypertension risk factors in some studies, or limited statistical power among many studies. Furthermore, hypertension is a public health issue of great relevance in Baleric Islands (Spain). For these reasons we performed an association study about the relationship between the M235T, T174M and G-6A diallelic polymorphisms of the angiotensinogen gene and hypertension in a population from Majorca (Balearic Islands), in which a considerable homogeneity with respect to ethnicity and environmental factors could be documented. This population was composed of 109 patients and 107 controls. Alleles of the angiotensinogen gene were determined by PCR and restriction site polymorphism analysis. The different genotypes were tested for association with dependent variables by univariate and multivariate logistic regression analysis. In the univariate analysis we found no evidence of association between the angiotensinogen gene genotypes and hypertension. This lack of association was independent of obesity, familial history of hypertension and diabetes for the genotypes of the polymorphisms M235T and G-6A; however, in the multivariate analysis the T174T174 genotype showed an almost significant positive association with hypertension [OR = 2.76 (95% confidence interval: 1.00-7.65, p = 0.05)]. The T174T174 genotype also showed a significant negative association with obesity [OR = 0.41 (95% confidence interval: 0.18-0.90, p = 0.03)] that remained after adjustment by sex, hypertension and diabetes [OR = 0.26 (95% confidence interval: 0.10-0.65, p = 0.004)]. Our results: a) are in contrast with the results from most previous studies that found a relationship of the T174M polymorphism with hypertension, as in those studies the M174 allele was responsible for the association; b) emphasize the need for rigorous control for obsesity in the studies of association between the angiotensinogen gene and hypertension; c) underscore the importance and the utility of using concrete populations to carry out studies on the genetic dissection of hypertension.

Topics: Adult; Aged; Angiotensinogen; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Polymorphism, Genetic; Spain

Several studies suggested the role of the genes of the rennin-angiotensin system in the pathogenesis of essential arterial hypertension.. We investigated 100 consecutive hypertensive patients (42 males and 58 females; mean +/- SD age, 55.14 +/- 9.49 years) for M235T and T174M polymorphisms. Seventy six normotensive patients (28 males and 48 females; mean +/- SD age, 54.94 +/- 9.56 years) formed the control group.. M235T and T174M polymorphisms were analyzed using PCR-RFLP methods.. The carrier frequency of M235T polymorphism in the AGT gene was 73% in hypertensive patients and 34.21% in normotensive patients (OR 5.2, 95%CI [2.72-9.93], p<0.01, chi2 test). The carrier frequency of T174M polymorphism in the AGT gene was 42% in hypertensive patients and 11.84% in normotensive patients (OR 5.39, 95%CI [2.41-12.01], p<0.01, chi2 test).. Essential arterial hypertension is associated with polymorphisms in the AGT gene, M235T and T174M.

Topics: Adult; Angiotensinogen; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Reference Values; Romania

Several association studies of candidate genes for preeclampsia and essential hypertension have led to discordant results, partly because of small sample sizes. Using a large population-based sample of pregnant women, we conducted an association study of 10 polymorphisms in 9 genes and aimed (1) to validate 10 published associations with preeclampsia or essential hypertension, (2) to investigate candidate polymorphisms previously associated with preeclampsia for association with essential hypertension and similarly with polymorphisms previously associated with essential hypertension. From a prospective sample of 3391 nulliparous French Canadian pregnant women, we identified 180 cases of preeclampsia, 203 cases of essential hypertension that were matched with normotensive control subjects (n=310 and 357, respectively). Polymorphisms were genotyped by allele-specific PCR. Among our candidate polymorphisms, the Met allele of Thr174Met of AGT was associated with preeclampsia (P=0.0033). Haplotype analysis revealed that the A-Met-Thr (G1035A-Thr174Met-Met235Thr) haplotype was associated with a 2.1-fold increased risk of preeclampsia (95% CI, 1.4 to 3.4; P=0.0008). In conclusion, we observed a strong association between a specific AGT haplotype and preeclampsia in our population, without replicating previous published associations with either preeclampsia or essential hypertension. Our data support a role for AGT in genetic susceptibility to preeclampsia.

Topics: Adult; Angiotensinogen; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Prospective Studies

Little is known about an in vivo significance of angiotensin II Type-1 receptor (AT1) for pregnancy-associated diseases, including hypertension and intrauterine growth retardation (IUGR). We previously demonstrated that female mice carrying the human angiotensinogen gene (hAG+/+), when mated with human renin transgenic (hRN+/+) male mice, displayed hypertension in late pregnancy due to secretion of human renin from the fetal side into the maternal circulation. In the present study, to investigate a role for AT1 in pregnancy-associated hypertension, we generated a new strain of hAG+/+/mAT1a-/- mice by genetically deleting the AT1a gene from hAG+/+ mice. When mated with hRN+/+ male mice, excessive increases in human renin, angiotensin, and plasma renin activity were detected in the plasma of pregnant hAG+/+/mAT1a-/- mice as found in that of pregnant hAG+/+ mice. Surprisingly, however, blood pressure of hAG+/+/mAT1a-/- mice was not elevated in late pregnancy despite the presence of AT1b, a subtype of AT1. The maternal and fetal defects, such as cardiac and placental abnormalities, and IUGR observed in pregnant hypertensive hAG+/+ mice were not recognized in pregnant hAG+/+/mAT1a-/- mice. The limited term administration of AT1 antagonists to hypertensive hAG+/+ mice in late pregnancy dramatically improved hypertension and IUGR, showing the clinical importance of AT1a.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Crosses, Genetic; Female; Fetal Growth Retardation; Gene Deletion; Humans; Hypertension; Male; Mice; Mice, Transgenic; Placenta; Pregnancy; Receptor, Angiotensin, Type 1; Renin

The objective of this study was to analyse the relationship of polymorphisms of the angiotensinogen (AGT) gene with the changes in microalbuminuria during 3 years of antihypertensive treatment in a group of young adults with essential hypertension.. Essential hypertensives, less than 50 years old, never previously treated with antihypertensive drugs and in the absence of diabetes mellitus were included. After the initial evaluation, patients were treated using only nonpharmacological measures (n=23), only beta-blockers (n=26), only angiotensin-converting enzyme inhibitors (ACEi) (n=57) or a combination of treatments (n=25). The office blood pressure, biochemical profile and urinary albumin excretion (UAE) were measured at the beginning and then yearly. The polymorphism A-6G of the AGT gene located in the promoter region was analysed.. In total, 131 patients, 35 (27%) microalbuminurics, were included. Although no significant differences in systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose and UAE were observed among genotypes at the initial examination, during the 3 years of antihypertensive treatment the slope values for the DBP, fasting glucose and UAE differed significantly despite no differences in the distribution of treatments being present. The subjects carrying the AA-6 genotype had the largest DBP decrease, but the lowest UAE reduction and the highest slope of glucose. Out of 35 initially microalbuminuric patients, 24 became normoalbuminuric and the lowest reduction rates were observed in subjects who carried the allele A-6. No interaction between the type of treatment and genotype was observed on the changes in UAE, BP or glucose values. In the subset of 57 patients treated with ACEi, the changes in UAE, BP and glucose had the same trend as was observed in the total population.. Subjects carrying the AA genotype of the A-6G AGT gene polymorphism are resistant to a reduction of microalbuminuria. Whether this can be attributed to a predisposition to glucose metabolic disturbance or not needs to be confirmed in further studies.

Topics: Adrenergic beta-Antagonists; Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Blood Glucose; Blood Pressure; Female; Follow-Up Studies; Genotype; Humans; Hypertension; Male; Polymorphism, Genetic; Time Factors; Treatment Outcome

In addition to central nervous system actions, angiotensin (Ang) II may increase sympathetic nerve activity (SNA) via a direct action on sympathetic ganglia. We hypothesized that sympathetic ganglionic actions of endogenous Ang II contribute to SNA in transgenic mice that overexpress renin and angiotensinogen (R+A+ mice). Renal SNA and arterial pressure were recorded in anesthetized R+A+ and littermate control mice before and after ganglionic blockade, and after additional blockade of angiotensin type 1 (AT1) receptors with losartan. Ganglionic blockade essentially abolished SNA in control mice, but only reduced SNA to 47+/-18% of baseline in R+A+ mice. The residual SNA remaining after ganglionic blockade in R+A+ mice was reduced from 47+/-18% to 8+/-6% of baseline by losartan (P<0.05). The sympathoinhibitory response to losartan was accompanied by an enhanced decrease in arterial pressure in R+A+ mice compared with that observed in control mice. AT1 receptor expression in sympathetic ganglia, as measured by real-time reverse transcription-polymerase chain reaction, was increased approximately 3-fold in R+A+ versus control mice. The results demonstrate that, as anticipated, essentially all of the renal postganglionic SNA in control mice is driven by preganglionic input. The major new finding is that Ang II-evoked ganglionic activity accounts for approximately 40% of total SNA in R+A+ mice. The significant contribution of the direct ganglionic action of Ang II in R+A+ mice likely reflects both increased levels of Ang II and upregulation of AT1 receptors in sympathetic ganglia.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Blood Pressure; Chlorisondamine; Ganglia, Sympathetic; Ganglionic Blockers; Humans; Hypertension; Kidney; Losartan; Mice; Mice, Transgenic; Renin; Renin-Angiotensin System; Sympathetic Nervous System

In the coarctation hypertension model, we showed both dissociation of plasma renin activity from cardiovascular-induced effects and the reversal of hypertension-induced responses by losartan. In this study, we investigated the effects of hypertension on the expression of brain renin-angiotensin system components and the simultaneous functional responses and effects of long-term angiotensin II (AT) receptor blockade on these responses. Rats were given vehicle or losartan for 9 days and subjected to subdiaphragmatic aortic constriction or sham surgery after 4 days of treatment. On the fifth postsurgical day, pressure and heart rate were measured in the conscious state; the brain was perfused and removed afterward. Sequential slices of brainstem were hybridized with 35S-oligodeoxynucleotide probes for angiotensinogen, AT1A, and AT1B receptors and processed for autoradiography and densitometry. In vehicle-treated rats, hypertension was accompanied by tachycardia and marked increments in angiotensinogen and AT1A mRNA expression in the cardiovascular system-controlling brainstem areas. In the nucleus tractus solitarii, AT1A density was correlated with both pressure and heart rate values (P<0.01), whereas angiotensinogen levels were correlated with pressure only (P<0.05). Losartan did not change the pressure of hypertensive rats (142+/-4 versus 146+/-2 mm Hg, losartan versus vehicle) and the hypertension-induced angiotensinogen mRNA expression but did block both tachycardic response and hypertension-induced AT1A mRNA expression. Hypertension and losartan did not change AT1B mRNA expression. The hypertension-induced positive feedback on angiotensinogen and AT1A mRNA expression supports the concept of a permissive role for brain angiotensin II in orchestrating circulatory responses during the development of hypertension. These data also explain the efficacy of long-term AT1 receptor blockade to reverse hypertension-induced effects.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Blood Pressure; Brain Stem; Gene Expression; Hypertension; Losartan; Male; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; RNA, Messenger; Solitary Nucleus

The renin-angiotensin-aldosterone (RAA) system regulates blood pressure (BP) levels and influences responses to antihypertensive medications. Variation in RAA system genes has been reported to influence interindividual differences in BP levels and the occurrence of hypertension (HTN).. We evaluated the relationship between variation in genes of the RAA system and interindividual differences in BP response to a thiazide diuretic. Analyses were carried out in a race- and gender-specific manner in 255 unrelated hypertensive African-Americans (125 men and 130 women) and 246 unrelated hypertensive non-Hispanic Whites (133 men and 113 women).. The angiotensin II receptor (AT(1)R) A1166C and angiotensinogen G-6A polymorphisms had a significant effect on systolic BP response to the diuretic in African-American women. Multilocus analyses indicated that the effects of these genes combined additively to influence response. Results of a permutation test to adjust for multiple comparisons and the possible nonindependence among genotypes remained significant at the P=0.003 level.. Among African-American women, particular gene variations in the RAA system have additive effects on BP response to a thiazide diuretic.

Topics: Adult; Angiotensinogen; Benzothiadiazines; Black or African American; Blood Pressure; Diuretics; Female; Genetic Markers; Genetic Variation; Hispanic or Latino; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; White People

Cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolites are involved in the regulation of renal vascular tone and salt excretion. The epoxygenation product 11,12-epoxyeicosatrienoic acid (EET) is anti-inflammatory and inhibits nuclear factor-kappa B activation. We tested the hypothesis that the peroxisome proliferator-activated receptor-alpha-activator fenofibrate (Feno) induces CYP isoforms, AA hydroxylation, and epoxygenation activity, and protects against inflammatory organ damage. Double-transgenic rats (dTGRs) overexpressing human renin and angiotensinogen genes were treated with Feno. Feno normalized blood pressure, albuminuria, reduced nuclear factor-kappa B activity, and renal leukocyte infiltration. Renal epoxygenase activity was lower in dTGRs compared to nontransgenic rats. Feno strongly induced renal CYP2C23 protein and AA-epoxygenase activity under pathological and nonpathological conditions. In both cases, CYP2C23 was the major isoform responsible for 11,12-EET formation. Moreover, we describe a novel CYP2C23-dependent pathway leading to hydroxy-EETs (HEETs), which may serve as endogenous peroxisome proliferator-activated receptor-alpha activators. The capacity to produce HEETs via CYP2C23-dependent epoxygenation of 20-HETE and CYP4A-dependent hydroxylation of EETs was reduced in dTGR kidneys and induced by Feno. These results demonstrate that Feno protects against angiotensin II-induced renal damage and acts as inducer of CYP2C23-mediated epoxygenase activities. We propose that CYP-dependent EET/HEET production may serve as an anti-inflammatory control mechanism.

Topics: 8,11,14-Eicosatrienoic Acid; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Arachidonic Acid; Blotting, Western; Chromatography, Liquid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Fenofibrate; Humans; Hypertension; Hypolipidemic Agents; Immunohistochemistry; Kidney; Kidney Diseases; Mass Spectrometry; NF-kappa B; Polymerase Chain Reaction; Rats; Receptors, Cytoplasmic and Nuclear; Renin; Transcription Factors; Vasoconstrictor Agents

The peroxisome proliferator activated receptor (PPARgamma) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R(+)A(+)). Rosiglitazone decreased systolic (138+/-5 versus 128+/-5 mm Hg) and mean blood pressure (145+/-5 versus 126+/-7 mm Hg) of R(+)A(+) mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R(+)A(+) mice when compared with littermate controls (RA(-)). There were no effects of rosiglitazone on RA(-) mice; however, relaxation to acetylcholine (49+/-10 versus 82+/-9% at 100 micromol/L) and nitric oxide (51+/-11 versus 72+/-6% at 10 micromol/L) was significantly improved in treated R(+)A(+) mice. Rosiglitazone treatment of R(+)A(+) mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R(+)A(+) and RA(-) mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPARgamma-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (200 micromol/L) or the PPARgamma antagonist bisphenol A diglycidyl ether; 4,4'-isopropylidenediphenol diglycidyl ether (100 micromol/L). These data suggest that in addition to potential genomic regulation caused by PPARgamma activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Endothelium, Vascular; Humans; Hypertension; Mice; Mice, Transgenic; Receptors, Cytoplasmic and Nuclear; Renin; Rosiglitazone; Thiazolidinediones; Transcription Factors; Vasodilation

Adipose tissue represents an important source of angiotensinogen (AGT). We investigated the effect of obesity induced by a high-fat diet on the expression of mouse (mAGT) and human AGT (hAGT) genes in liver, kidney, and heart and different adipose depots in normal mice (C57BL/6J), and in transgenic mice expressing the hAGT gene under the control of its own promoter. Mice were fed a high-fat diet (45% kcal) or normal chow (10% kcal) for 10 and 20 wk. The expression of mAGT and hAGT mRNA was quantified using an RNAse protection assay. Mice on the high-fat diet exhibited increased weight, fat mass, and plasma leptin. Expression of mAGT or hAGT genes was not affected by high-fat diet in nonadipose tissues, brown adipose tissue, or subcutaneous white fat. In contrast, high-fat diet increased both mAGT and hAGT gene expression in visceral adipose depots (omental, reproductive, and perirenal fat). Thus obesity-induced by a high-fat diet is associated with a tissue-specific increased expression of both mouse and human AGT genes in intra-abdominal adipose tissue. Our findings also suggest that 1.2 kb of regulatory sequences present in the hAGT transgene are sufficient to transcriptionally respond to a high-fat diet in an adipose-specific and depot-specific manner.

Topics: Adipose Tissue; Angiotensinogen; Animals; Body Weight; Dietary Fats; Gene Expression; Hypertension; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; RNA, Messenger

To investigate whether the variants A(-6)G and A(-20)C of angiotensinogen (AGT) gene are involved in the pathogenesis of essential hypertension in Kazakans.. T his case control study recruited 125 subjects with hypertension and 74 normotensive subjects from Kazakans of Xinjiang. Genomic DNA from leukocytes was analyzed for genetic variants A(-6)G and A(-20)C in 5' upstream core promoter of AGT gene by polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP), restriction fragment length polymorphism (RFLP) and automatic sequencing.. (1)There were only A(-6)G and A(-20)C variants in the -164 to +73 region of Kazakans' AGT gene. (2) The distributions of genotypes AA, AG, GG at locus -6 of AGT gene showed significant difference between the hypertensive group (0.39, 0.45, 0.16) and the normotensive group (0.49, 0.49, 0.02; Chi2=8.56, P=0.014). There were evident differences in the frequencies of the -6A and the -6G allele of the two groups (0.62, 0.38 and 0.73, 0.27; Chi2=5.35, P=0.021). (3) No significant difference was observed in the distribution of genotypes AA, AC, CC at locus -20 of AGT gene between the hypertensive group (0.69, 0.26, 0.05) and the normotensive group (0.65, 0.32, 0.03; Chi2=2.42, P=0.30). There was no distinct difference in the frequencies of the -20A allele and the -20C allele of the two groups (0.82, 0.18 and 0.82, 0.18; Chi2=0, P=0.99). (4) No significant difference was found at the levels of systolic and diastolic blood pressure between the groups corresponding to genotypes at the loci -6 and -20 of AGT gene.. The results suggest that the polymorphism of A(-6)G in 5' upstream core promoter of the AGT gene may be involved in the pathogenesis of essential hypertension in Kazakans, while the A(-20)C variant may not play an important role in the etiology of essential hypertension in Kazakans.

Topics: 5' Flanking Region; Adult; Alleles; Angiotensinogen; Base Sequence; Blood Pressure; Case-Control Studies; China; DNA; DNA Mutational Analysis; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic

Although some single polymorphism analyses of the angiotensinogen (AGT) gene have been found to be associated with hypertension, the results are still inconsistent. The objectives of this study are to evaluate the association of the genotype and haplotype distributions of three single-nucleotide polymorphisms (SNPs) (G-217A, A-6G, and M235T) in the AGT gene with hypertension. In a sample of 461 hypertensive and 327 normotensive patients in Taiwan, we found that -217AA and -6GG homozygotes conferred independently an increased risk to hypertension (P = 0.008 and P = 0.037, respectively), as illustrated by their significant associations with hypertension in both single SNP and pair-wise SNPs analyses. Meanwhile, a very weak linkage disequilibrium was found between the G-217A and the A-6G polymorphisms in terms of r2 (<0.05). On the basis of likelihood ratio test, only the set of haplotypes that constituted the A-6G and the M235T polymorphisms was associated with hypertension (chi2 = 20.91, P = 0.0008), which was mainly due to the increased frequency of the recombinant haplotypes (-6A identical with 235M and -6G identical with 235T), and a pathophysiological role in the predisposition to hypertension was hence indicated. In functional assays, the promoter activities of the haplotypes -217A identical with -6A and -217G identical with -6G were significantly higher than the most common haplotype -217G identical with -6A. These results highlight the necessity of a thorough analysis of all reported variants of a candidate gene in the elucidation of genetic susceptibility to a complex disease like hypertension, even when the variants are in the same haplotype block.

Topics: Angiotensinogen; Cell Line, Tumor; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Transcription, Genetic

We have recently reported that Dahl salt-sensitive rats (DS) on high salt diet (HS) have an inappropriate augmentation of intrarenal angiotensinogen. Recent studies also reported that the augmented superoxide anion formation plays important roles in this animal model of hypertension. This study was performed to address the hypothesis that an inappropriate augmentation of intrarenal angiotensinogen by HS is caused by the augmented reactive oxygen species. Male DS (200-220 g) were maintained on low salt diet LS (N = 7) or HS (N = 27) for 4 weeks. The HS group was subdivided into three subgroups to receive null (N = 12), superoxide dismutase mimetic, tempol (3 mmol/l, N = 8), or vasodilator, hydralazine (0.5 mmol/l, N = 7) in drinking water during the period. Systolic BP was significantly increased in the DS+HS group compared to the DS+LS group (184+/-7 mmHg vs. 107+/-5 at 4-week). Tempol or hydralazine treatment equivalently attenuated the hypertension (128+/-3 and 127+/-5 at 4-week, respectively). Urinary excretion of thiobarbituric acid reactive substances at 4-week was significantly increased in the DS+HS group compared to the DS+LS group (0.66+/-0.05 micromol/day vs. 0.14+/-0.01). Tempol treatment prevented this effect (0.24+/-0.04) but hydralazine treatment only partially prevented the effect (0.40+/-0.03). Kidney angiotensinogen levels, measured by Western blot analysis, were significantly increased in the DS+HS group compared to the DS+LS group (32+/-5 densitometric units vs. 21+/-1). Tempol (14+/-3) but not hydralazine (32+/-5) treatment prevented the intrarenal angiotensinogen augmentation. The evidence suggests that the enhanced intrarenal angiotensinogen in DS challenged with HS is associated with the augmented reactive oxygen species.

Topics: Actins; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Cyclic N-Oxides; Hydralazine; Hypertension; Kidney; Male; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Spin Labels; Thiobarbituric Acid Reactive Substances

Angiotensin (Ang) II-infused hypertensive rats exhibit increases in renal angiotensinogen mRNA and protein, as well as urinary angiotensinogen excretion in association with increased intrarenal Ang II content. The present study was performed to determine if the augmentation of intrarenal angiotensinogen requires activation of Ang II type 1 (AT1) receptors. Male Sprague-Dawley rats (200 to 220 g) were divided into 3 groups: sham surgery (n=10), subcutaneous infusion of Ang II (80 ng/min, n=11), and Ang II infusion plus AT1 blocker (ARB), olmesartan (5 mg/d, n=12). Ang II infusion progressively increased systolic blood pressure (SBP) compared with sham (178+/-8 mm Hg versus 119+/-4 at day 11). ARB treatment prevented hypertension (113+/-6 at day 11). Twenty-four-hour urine collections were taken at day 12, and plasma and tissue samples were harvested at day 13. The Ang II+ARB group had a significant increase in plasma Ang II compared with Ang II and sham groups (365+/-46 fmol/mL versus 76+/-9 and 45+/-14, respectively). Nevertheless, ARB treatment markedly limited the enhancement of kidney Ang II by Ang II infusion (65+/-17 fmol/g in sham, 606+/-147 in Ang II group, and 288+/-28 in Ang II+ARB group). Ang II infusion significantly increased kidney angiotensinogen compared with sham (1.69+/-0.21 densitometric units versus 1.00+/-0.17). This change was reflected by increased angiotensinogen immunostaining in proximal tubules. ARB treatment prevented this increase (1.14+/-0.12). Urinary angiotensinogen excretion rates were enhanced 4.7x in Ang II group (4.67+/-0.41 densitometric units versus 1.00+/-0.21) but ARB treatment prevented the augmentation of urinary angiotensinogen (0.96+/-0.23). These data demonstrate that augmentation of intrarenal angiotensinogen in Ang II-infused rats is AT1-dependent and provide further evidence that urinary angiotensinogen is closely linked to intrarenal Ang II in Ang II-dependent hypertension.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Hypertension; Imidazoles; Kidney; Kidney Tubules, Proximal; Male; Olmesartan Medoxomil; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Tetrazoles

Evidence on the effect of salt intake on the interaction between angiotensinogen (AGT) T174M polymorphism and high blood pressure is sparse. We therefore conducted a large population-based cross-sectional study of 2,823 men and women aged 30-74 in a Japanese farming community to examine associations between AGT polymorphism and blood pressure levels stratified by age (30-64 and 65-74), body mass index (BMI; median), and salt intake (median) estimated by 24-h urine collection and dietary questionnaire. Our a priori hypothesis is that individuals, particularly younger and non-overweight individuals, with the 174M allele have elevated blood pressure levels in response to higher sodium intake, and thus the association between T174M polymorphism and blood pressure is more evident among individuals with higher sodium intake than those with lower sodium intake. There were no differences in systolic or diastolic blood pressure levels (SBP or DBP) between the TT and TM+MM genotype groups overall. However, the mean difference in DBP between the TM+MM and TT groups was +1.0 mmHg in subjects of younger age (p=0.06), +1.7 mmHg in non-overweight subjects (BMI<23.5 kg/m2, p=0.01), and +2.3 mmHg in younger and non-overweight subjects (p = 0.002). Furthermore, among younger and non-overweight subjects, blood pressure differences were larger for those with higher urinary sodium excretion (+3.1 mmHg, p = 0.03), those with a higher sodium/potassium excretion ratio (+4.1 mmHg, p=0.007), those with higher present sodium intake score (+3.0 mmHg, p=0.003), and those with higher past sodium intake score (+3.4 mmHg, p<0.001). In conclusion, AGT T174M polymorphism was associated with higher DBP levels in younger and non-overweight Japanese. This association was more evident among subjects with higher sodium intake.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Body Weight; Female; Genotype; Humans; Hypertension; Japan; Male; Middle Aged; Polymorphism, Genetic; Rural Population; Sodium, Dietary

To investigate the association of the AGT gene M235T variant with essential hypertension in Han population of Zhejiang Province.. The study included 230 subjects: 116 hypertensive patients and 114 normotensive controls. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to detect the M235T variant of angiotensinogen (AGT) gene. Blood pressure, body height and weight, fasting blood glucose and serum lipid were measured in all subjects.. (1)The systolic blood pressure and diastolic blood pressure of hypertensive group were significantly higher than those of control group, while no significant difference was observed with regard to age, gender, body mass index, blood glucose, or lipid profile. (2)The genotype distribution of AGT gene in both groups was in agreement with Hardy-Weinberg equilibrium. (3)The genotype distribution of the M235T variant differed significantly in hypertensives and controls (chi(2)=6.966,P<0.05). The frequencies of genotype TT and T235 allele in hypertensives were higher than those in controls (TT genotype: 0.47 compared with 0.33, chi(2)=5.36,P<0.05; T235 allele: 0.71 compared with 0.60, chi(2)=6.179, P<0.05).. The molecular variant M235T of the AGT gene is significantly associated with essential hypertension in this population. The genotype TT or allele T235 might be a genetic risk factor for hypertension.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

To evaluate the relationship of six single nucleotide polymorphisms(SNPs) and their haplotypes of angiotensinogen(AGT) gene to essential hypertension(EH) in Chinese Han population.. The genotypes in 185 patients with EH and 185 healthy controls were determined by the method of ABI PRISM SNaPshot Multiplex Kit using six AGT gene polymorphisms at position -217(G/A), -152(G/A), -20(A/C) and -6(G/A) in the promoter region and T174M, M235T in exon 2.. The distribution of AGT genotypes and alleles frequencies showed no significant difference between the group of EH and group of controls (P>0.05). However, haplotype analysis revealed that H4 haplotype frequency, which included -152A, -20C, -6A and 235T alleles, was significantly increased in the group of EH (P<0.05).. G-152A, A-20C, G-6A and M235T polymorphisms of AGT gene might play an important role in the occurrence of EH in Chinese Han population.

Topics: Adult; Aged; Angiotensinogen; Female; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide

We investigated the role of gene polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen, endothelial NO (eNO) synthase, and bradykinin receptor B2 in determining the cardiovascular system structure and function in hypertension and "athletic heart" syndrome. Using a PCR-based method, 114 hypertensive patients and 94 athletes were genotyped for I/D polymorphism of ACE, M235T angiotensinogen (ANG), Glu298 Asp endothelial synthase (eNOS), and type 2 receptor for bradykinin (BDKR2). Echocardiography and a 24 hour blood pressure monitoring being performed. The (+)-allel of BDKR2 gene was associated with the left ventricular hypertrophy and greater wall thickness in athletes and hypertensive subjects. The hypertensive patients, that were homozygous for Glu298 allele of eNOS, demonstrated a lower level of diastolic blood pressure than did those with Glu298 Asp and Asp298 Asp genotypes. At the same time, the ACE and AND gene polymorphisms displayed no association with the cardiac structure and function.

Topics: Adult; Alleles; Angiotensinogen; Blood Pressure; Female; Genetic Predisposition to Disease; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardium; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptor, Bradykinin B2; Sports Medicine

We have previously reported that hypertension in the young spontaneously hypertensive rat (SHR) is associated with an elevation in tissue angiotensinogen and a novel polysomal protein known to stabilize angiotensinogen mRNA. In our current study we determined the role of the mRNA-stabilizing protein in the regulation of tissue angiotensinogen expression and mean arterial pressure (MAP) in the SHR utilizing antisense oligodeoxynucleotide (AON) inhibition. Three AONs (RNASTAAS1, position 31-50; RNASTAAS2, position 21-40; RNASTAAS3, position 143-162 of the cDNA coding for the polysomal protein) were administered intravenously (dose 450, 900, and 1,800 microg/kg; 1 dosage/day over 3 days) in conscious, chronically instrumented male SHRs at the age of 7 wk. Control SHRs received corresponding scrambled oligodeoxynucleotide sequences (SCR1, SCR2, SCR3). Each animal received the increasing dose schedule. RNASTAAS2 resulted in a reduced expression of the polysomal protein to 21% (liver), 12% (brain), 27% (heart), 18% (renal cortex), and 22% (renal medulla) of control. Angiotensinogen expression was inhibited to 54% (liver), 41% (brain), 68% (heart), 52% (renal cortex), and 74% (renal medulla) compared with control SHRs. Decreases in plasma concentrations of angiotensinogen and plasma renin activities were associated with a significant decrease in MAP from 147 +/- 6 mmHg (after SCR2) to 106 +/- 4 mmHg after RNASTAAS2. The effects of the two other AONs on MAP were less (RNASTAAS1, -31 mmHg; RNASTAAS3, -16 mmHg) with corresponding decreases in mRNAs coding for angiotensinogen and the polysomal protein. A significant decrease in intracellular concentrations of the polysomal protein accompanied AON inhibition. The magnitude of effects (-15 to -41 mmHg) was comparable to the effects of captopril (100 mg x kg(-1) x day(-1) for 3 days: -32 mmHg) and an AT(1) receptor antagonist (L-158809, 1.5 mg x kg(-1) x day(-1) for 3 days: -36 mmHg). These data suggest an important role of the mRNA-stabilizing protein for hepatic and extrahepatic angiotensinogen expression and MAP in the SHR.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Hypertension; Imidazoles; Liver; Male; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA Stability; RNA, Messenger; Tetrazoles

In obesity-related hypertension, activation of the renin-angiotensin system (RAS) has been reported despite marked fluid volume expansion. Adipose tissue expresses components of the RAS and is markedly expanded in obesity. This study evaluated changes in components of the adipose and systemic RAS in diet-induced obese hypertensive rats. RAS was quantified in adipose tissue and compared with primary sources for the circulating RAS. Male Sprague-Dawley rats were fed either a low-fat (LF; 11% kcal as fat) or moderately high-fat (32% kcal as fat) diet for 11 wk. After 8 wk, rats fed the moderately high-fat diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups based on their body weight gain (body weight: OR, 566 +/- 10; OP, 702 +/- 20 g; P < 0.05). Mean arterial blood pressure was increased in OP rats (LF: 97 +/- 2; OR: 97 +/- 2; OP: 105 +/- 1 mmHg; P < 0.05). Quantification of mRNA expression by real-time PCR demonstrated a selective increase (2-fold) in angiotensinogen gene expression in retroperitoneal adipose tissue from OP vs. OR and LF rats. Similarly, plasma angiotensinogen concentration was increased in OP rats (LF: 390 +/- 48; OR: 355 +/- 24; OP: 530 +/- 22 ng/ml; P < 0.05). In contrast, other components of the RAS were not altered in OP rats. Marked increases in the plasma concentrations of angiotensin peptides were observed in OP rats (angiotensin II: LF: 95 +/- 31; OR: 59 +/- 20; OP: 295 +/- 118 pg/ml; P < 0.05). These results demonstrate increased activity of the adipose and systemic RAS in obesity-related hypertension.

Topics: Adipose Tissue; Angiotensinogen; Animals; Autoradiography; Blood Pressure; Cholesterol; Diet; DNA Primers; Gene Expression Regulation; Hemodynamics; Hypertension; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA; Weight Gain

The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for blood pressure (BP) regulation and essential hypertension.. To investigate whether AGT haplotype analysis adds significant information compared to single polymorphism analysis with respect to different BP phenotypes in an untreated hypertensive sample.. Two hundred and twelve untreated hypertensive subjects of Caucasian origin were genotyped for the AGT polymorphisms C-532T, A-20C, C-18T, and G-6A.. In single variant analyses, untreated hypertensives, carrying the AGT -532T or -6A alleles had significantly higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as ambulatory BP values compared to respective non-carriers. In haplotype-based analyses, combining all four AGT promoter variants, we demonstrate that AGT haplotypes containing different allele combinations at positions -532 and -6 were significantly associated with different BP values: (1) -532T and -6A with higher, (2) -532C and -6G with lower, (3) -532C and -6A with intermediate BP values. Since the result for the -532C/-20A/-18C/-6G haplotype was due to differences between non-carriers and carriers of this haplotype on both chromosomes, a recessive inheritance model for BP effects could be assumed.. Our results designate the C-532T and G-6A as the best candidates for functional studies on the AGT gene. Haplotype-based analyses should greatly aid in the dissection of the genetic basis of complex traits, such as BP regulation and hypertension.

Topics: Adult; Angiotensinogen; Blood Pressure; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Middle Aged; Phenotype; Polymorphism, Genetic; Predictive Value of Tests; Promoter Regions, Genetic; White People

To determine whether carotid artery stiffness was increased in patients with untreated essential hypertension who are homozygous for the T allele of the M235T polymorphism of the angiotensinogen (AGT) gene and in mutant mice carrying three copies of the angiotensinogen (Agt) gene.. Using echotracking systems, we studied carotid mechanical properties in 98 never-treated hypertensive patients according to their AGT genotype, and in Agt mutant mice.. Patients homozygous for the T allele had a reduced carotid distensibility and an increased stiffness of the carotid wall material (Young's elastic modulus), independent of blood pressure, compared with patients homozygous for the M allele. In Agt1/2 mice, carotid distensibility was not significantly different from that of Agt1/1 (wild-type). Moreover, the stiffness of the arterial wall material was lower in Agt1/2 mice than in wild-type mice. In Agt1/2 mice, the greater blood pressure was not associated with arterial hypertrophy, resulting in a greater circumferential wall stress. The in-vivo and in-vitro pressor responses to angiotensin II were reduced in Agt1/2 mice, whereas the contractile response to phenylephrine was not significantly different between Agt1/1 and Agt1/2 mice, indicating the integrity of the contractile apparatus and suggesting a dysfunction of the angiotensin II type 1 receptor signalling pathways in Agt1/2 mice.. These data suggest that the angiotensinogen TT genotype at position 235 could be a genetic marker for arterial stiffness in patients with never-treated hypertension, whereas in Agt1/2 mice the dysfunction of the angiotensin II type 1 receptor signalling pathways could explain the lack of arterial wall hypertrophy and stiffness.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Animals; Carotid Arteries; Disease Models, Animal; Female; Genotype; Homozygote; Humans; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Signal Transduction

To evaluate the potential implications of the genetic variability of angiotensin converting enzyme, angiotensinogen and angiotensin II type 1 receptor gene for essential hypertension in Tibetan.. A case-control study was conducted in 173 hypertensive individuals and 193 individuals with normal blood pressure. Multiple logistic regression analyses were used to estimate the risks of developing hypertension for different genotypes, and haplotype analyses of the angiotensinogen gene were used to determine the association between two-locus angiotensinogen gene polymorphisms and hypertension.. As to the risk to high blood pressure and high systolic pressure, women with MM genotype were 7.7 (95% CI: 1.3-20.5) and 8.7 (95% CI: 1.8-20.1) times higher than those with TT genotype after adjustment for age and body mass index. Haplotype frequencies for M235T and G-6A were significantly different between hypertensive individuals and controls, which indicated an association of angiotensinogen gene haplotypes with hypertension, and a significant association of 235T/-6A haplotype with hypotensive effect.. Our results suggest that angiotensinogen gene 235MM is a predictor for hypertension development in Tibetan women but not in men, and may exert its hypertensive effect on linkage disequilibrum with a possible function locus of G-6A.

Topics: Adult; Aged; Angiotensinogen; Case-Control Studies; China; DNA; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sex Factors; Tibet

Topics: Adult; Angiotensinogen; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Coronary Angiography; Coronary Disease; Endothelium, Vascular; Genotype; Heat-Shock Proteins; Hemodynamics; Humans; Hypertension; Male; Myocardial Infarction; Nitric Oxide; Platelet Aggregation; Risk Factors; Vasodilation

Present studies examined the DNA polymorphisms in the AGT genes in a Chinese population in Henan province of central China. By using PCR-RFLP and maximum likelihood estimation (MLE), we estimated the pattern of intragenic linkage disequilibrium and the haplotype structure and explored the possible association between the polymorphisms of AGT gene and essential hypertension in a case-control study. Seven polymorphic sites (SNPs) and seven major haplotypes of AGT gene were analyzed. Among the individual SNP pairs examined, the A-6G, C+31T and M235T are nearly completely disequilibrium. All those single polymorphism loci were individually not associated with hypertension. But we found the frequency of haplotype H2 (-217: G, -152: G, -20: A, -6: G, +31: T, 174: T, 235: M) was significantly higher in controls than patients (P=0.010). Our study suggested that few haplotypes derived seven polymorphism loci could account for the most of the variation in AGT gene in Chinese Hans. The haplotype H2 of AGT gene might represent or be in disequilibrium with a genetic protective factor against EH.

Topics: Adult; Angiotensinogen; Asian People; China; Female; Gene Frequency; Haplotypes; Humans; Hypertension; Likelihood Functions; Linkage Disequilibrium; Male; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide

There are many reports demonstrating the association of renin-angiotensin system gene polymorphisms with hypertension in different populations. In the present study, we used haplotype analyses of the angiotensinogen gene with a new permutation-based hypothesis testing method to determine the association between multilocus angiotensinogen gene polymorphisms and hypertension in a relatively homogeneous Taiwanese population. We also genotyped angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin II type 1-receptor gene A1166C polymorphism to detect epistatic gene-gene interactions. There were 408 patients with hypertension (hypertensives) and 286 controls. The angiotensinogen gene haplotype frequencies were significantly different between hypertensives and controls, and this finding was only present in subjects with angiotensin-converting enzyme gene II genotypes when the analysis was stratified by genotype of this polymorphism. In addition, the angiotensinogen gene haplotype structure of hypertensives was more heterogeneous than that of controls. Our results showed that angiotensinogen gene haplotypes were associated with hypertension and might act synergistically with I allele of the angiotensin-converting enzyme gene.

Topics: Alleles; Angiotensinogen; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin

The genetic mechanisms underlying interindividual blood pressure variation among humans may reflect, at least in part, clustering of functional gene variants belonging to complex blood pressure control systems. In this study, we investigated the association of specific functional gene variants of the renin-angiotensin system, ACE (I/D) and angiotensinogen (M/T) genes, with blood pressure phenotypes (systolic, mean, diastolic, and pulse pressure), in an ethnically mixed urban population in Brazil. Individuals (n=1421) were randomly selected from the general population of the Vitoria City Metropolitan area. Neither gender, age, smoking status, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, or diabetes was associated with ACE or AGT polymorphism in univariate analysis. No association was found between ACE variants and blood pressure phenotypes. However, a statistically significant association was revealed between the AGT 235T variant and all blood pressure phenotypes, consistent with an additive/codominant mode of action even after adjustment for age and gender (P<0.01). Genotypic analysis contemplating both ACE and AGT variants in the same model did not show any significant interaction between both genetic polymorphisms. In addition, the AGT 235T allele was significantly associated with hypertension in a recessive model, which remained as an independent risk factor for hypertension even after adjustment for age, gender, and ethnicity (OR, 1.33; 95% CI, 1.04 to 1.70). Taken together, these data indicate a linear relation between AGT 235T allele number ("dosage") and blood pressure in an ethnically mixed urban population and confirmed its role as an independent risk factor for hypertension for men and women when in homozygosity.

Topics: Adult; Alleles; Amino Acid Substitution; Angiotensinogen; Blood Pressure; Cross-Sectional Studies; Female; Gene Dosage; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Genetic; Sequence Deletion

Angiotensin II (AngII) infusions augment renal angiotensinogen mRNA and protein and urinary angiotensinogen excretion (U(AGT)). Further experiments were performed in 4 groups of rats: normal salt diet with sham operation, NS+Sham, n=6; NS with AngII infusion at 40 ng/min via osmotic minipump, NS+AngII(40), n=9; NS with AngII infusion at 80 ng/min, NS+AngII(80), n=9; high-salt diet with deoxycorticosterone acetate salt pellet (100 mg), HS+DOCA, n=4. These experiments sought to determine whether enhanced U(AGT) is specifically associated with increased kidney AngII levels or is a nonspecific consequence of the hypertension. Systolic BP (SBP) was significantly increased to 131+/-2 and 162+/-2 mm Hg at day 11 in NS+AngII(40) and NS+AngII(80), respectively, compared with NS+Sham (110+/-1). Regression analysis demonstrated a positive relationship (R=0.49) between SBP and U(AGT) for NS+Sham (1.1+/-0.3 nmol AngI/d), NS+AngII(40) (2.5+/-0.9), and NS+AngII(80) (5.5+/-1.5). U(AGT) was also highly correlated (R=0.70) with kidney AngII content for NS+Sham (49+/-6 fmol/g), NS+AngII(40) (215+/-49), and NS+AngII(80) (347+/-47); but not with plasma AngII (R=0.12). HS+DOCA rats also exhibited increased SBP to 134+/-1 mm Hg, but U(AGT) (1.4+/-0.4 nmol AngI/d) and intrarenal AngII content (13+/-2 fmol/g) were not increased despite the hypertension. Infused human angiotensinogen could not be detected in urine of sham-operated or AngII-infused rats (n=4 each). These data demonstrate that U(AGT) increases in AngII-dependent hypertension in a dose- and time-dependent manner, but not in hypertension elicited by HS+DOCA. The results support the hypothesis that AngII-dependent hypertension results in elevated intrarenal AngII and angiotensinogen levels, reflected by increased U(AGT), which does not occur in an AngII-independent hypertensive model.

Topics: Angiotensin II; Angiotensinogen; Animals; Antibodies; Biomarkers; Blood Pressure; Blotting, Western; Dose-Response Relationship, Drug; Hemodynamics; Hypertension; Kidney; Kinetics; Male; Rats; Rats, Sprague-Dawley

We examined the hypothesis that the renin-angiotensin system plays an important role in vascular remodeling (defined as reduced external diameter) during chronic hypertension. We measured pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in transgenic mice that overexpress both human renin and human angiotensinogen and in spontaneously hypertensive mice, a model of chronic hypertension that is thought to develop independently of the renin-angiotensin system. Systemic arterial pressure under conscious conditions was increased by similar amounts in transgenically hypertensive mice (153+/-6 versus 117+/-4 mm Hg in controls; mean+/-SE, P<0.05) and spontaneously hypertensive mice (148+/-5 versus 112+/-5 mm Hg; P<0.05). The external diameter of maximally dilated cerebral arterioles was reduced in transgenically hypertensive mice (52+/-2 versus 66+/-3 micro m; P<0.05), but not in spontaneously hypertensive mice (58+/-4 versus 60+/-4 micro m; P>0.05). The cross-sectional area of the vessel wall was increased in both transgenically hypertensive mice (504+/-53 versus 379+/-37 microm2; P<0.05) and spontaneously hypertensive mice (488+/-40 versus 328+/-38 microm2; P<0.05). During maximal dilatation, the stress-strain curves in cerebral arterioles of transgenically hypertensive mice and spontaneously hypertensive mice were shifted to the right of the curves in corresponding controls, an indication that arteriolar distensibility was increased in the transgenically and spontaneously hypertensive groups. Thus, cerebral arterioles undergo remodeling and hypertrophy in transgenically hypertensive mice, but only hypertrophy in spontaneously hypertensive mice. These findings support the hypothesis that the renin-angiotensin system is an important determinant of vascular remodeling during chronic hypertension.

Topics: Angiotensinogen; Animals; Arterioles; Blood Pressure; Chronic Disease; Humans; Hypertension; Hypertrophy; Mice; Mice, Transgenic; Renin; Renin-Angiotensin System; Telencephalon; Vasodilation

Endothelin-1 is involved in mechanical load-induced cardiac growth processes; it also has effects on contractility. The interaction of endothelin-1 and the Frank-Starling response is unknown. The present study aimed to characterize the role of endothelin-1 in the regulation of the Frank-Starling response, one of the major mechanisms regulating cardiac contractile force, in both normal and hypertrophied hearts. Nontransgenic rat hearts and hypertrophic hearts of hypertensive double transgenic rats harboring human angiotensinogen and renin genes were studied in a Langendorff isolated heart setup with a liquid-filled balloon inside the left ventricle used to measure contractile parameters. The rats were studied at compensated phase, before showing any signs of heart failure. Compensated hypertrophy in double transgenic rat hearts resulted in improved contractility at a given level of preload when compared with nontransgenic rat hearts. Hearts of both rat lines showed preserved Frank-Starling responses, that is, increased contractile function in response to increased end-diastolic pressure. The mixed endothelin A/B receptor antagonist bosentan attenuated the Frank-Starling response by 53% (P<0.01) in the double transgenic hearts but not in nontransgenic hearts. The diastolic parameters remained unaffected. The left ventricles of the double transgenic rat hearts showed an 82% higher level of endothelin type A receptor mRNA and a 25% higher level of immunoreactive endothelin-1 compared with nontransgenic rat hearts. The type 1 angiotensin II receptor antagonist CV-11974 had no significant effect on contractile function in response to load in either strain. These results show that endogenous endothelin-1 contributes to the Frank-Starling response in hypertrophied rat hearts by affecting systolic performance.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Animals, Genetically Modified; Benzimidazoles; Biphenyl Compounds; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardial Contraction; Organ Culture Techniques; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; RNA, Messenger; Stress, Mechanical; Sulfonamides; Tetrazoles

The renin-angiotensin system is involved in adipocyte growth and differentiation and possibly in adipose tissue metabolism.. To investigate the association of polymorphism in the angiotensin-converting enzyme (ACE) I/D gene, angiotensinogen M235T gene, and angiotensin II type 1 receptor A1166C gene with body mass index, body fat pattern, and obesity-associated hypertension.. Cross-sectional longitudinal study.. The Olivetti factories in Marcianise and Pozzuoli, suburbs of Naples, Italy.. 959 adult men, 25 to 75 years of age.. Renin-angiotensin system polymorphism, anthropometric indexes, blood pressure, and serum glucose and insulin levels.. No association was detected between angiotensinogen or angiotensin II type 1 receptor gene polymorphism and anthropometric indexes or blood pressure. For ACE I/D polymorphism, significant age-genotype interaction was detected on cross-sectional observation; the relation of body mass index, waist circumference, and diastolic blood pressure to age was significantly greater in persons with the DD genotype than in those with the ID or II genotype. Overweight and abdominal adiposity were more common in men with the DD genotype, particularly among older participants (51.1% vs. 36.5% and 33.1% vs. 22.0%, respectively). Odds ratios were 1.82 (95% CI, 1.16 to 2.87) for overweight and 1.76 (CI, 1.06 to 2.90) for abdominal adiposity. Among 314 untreated men first examined 20 years earlier, those with the DD genotype had greater age-adjusted weight gain (1.45 kg [CI, 0.12 to 2.78 kg]) and change in diastolic blood pressure (2.83 mm Hg [CI, 0.39 to 5.28 mm Hg]). The relative risk for overweight was 2.34 (CI, 1.32 to 4.15) among participants with the DD genotype versus those with the ID or II genotype.. The ACE I/D polymorphism was a significant predictor of overweight and abdominal adiposity in men. DD homozygosity was associated with larger increases in body weight and blood pressure in aging persons, as well as with higher incidence of overweight.

Topics: Abdomen; Adipose Tissue; Adult; Aged; Angiotensinogen; Anthropometry; Body Weight; Cross-Sectional Studies; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Obesity; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System

Topics: Abdomen; Adipose Tissue; Adult; Aged; Angiotensinogen; Anthropometry; Body Weight; Humans; Hypertension; Male; Middle Aged; Obesity; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System

Albumin excretion is modulated post-filtration by lysosomal processing that produces a spectrum of albumin-derived material in urine, much of which is not detected by conventional immunoassays. This study aimed to determine the efficacy of ramipril treatment (+ RAM) after 24 weeks on total albumin excretion (intact plus albumin-derived peptides) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with (d) and without (c) diabetes.. Intact albumin excretion was analysed by radioimmunoassay and total albumin excretion was analysed by measuring radioactivity derived from circulating [ C]albumin. Renal lysosomal activity was determined by urinary [ H]dextran sulphate desulphation. Renal transforming growth factor-beta 1 (TGF-beta 1), TGF-beta inducible gene-h3 (beta ig-h3) and angiotensinogen mRNA production were analysed by real time reverse transcriptase-polymerase chain reaction.. Hypertension (SHR-c and SHR-d) resulted in a significant increase in intact albumin excretion, which was significantly reduced by ramipril treatment (P < 0.05 for SHR-c + RAM and 0.001 for SHR-d + RAM compared to non-treated). This was accompanied by a significant decrease in blood pressure (P < 0.001 for SHR-c + RAM and SHR-d + RAM), renal beta ig-h3 mRNA production (P < 0.05 for SHR-c + RAM and SHR-d + RAM), and an increase in lysosomal activity. Diabetes (WKY-d and SHR-d) primarily caused a significant increase in total albumin excretion, predominantly in the form of albumin-derived fragments in the WKY-d group and intact albumin in the SHR-d group. Ramipril treatment reduced total albumin excretion in the WKY-d + RAM group (P < 0.001).. Ramipril prevents increases in both intact albumin and total albumin excretion in hypertensive and diabetic states, respectively.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus; Extracellular Matrix Proteins; Hypertension; Lysosomes; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

The aim of the present study was to assess our hypothesis that the renin-angiotensin system (RAS) is responsible for cold-induced hypertension and cardiac hypertrophy. Two groups of wild-type (WT) mice and 2 groups of angiotensinogen gene knockout (Agt-KO) mice (6 per group) were used. After blood pressures (BP) of the four groups were measured 3 times at room temperature (25 degrees C), 1 WT and 1 Agt-KO group were exposed to cold (5 degrees C). The remaining groups were kept at 25 degrees C. BP of the cold-exposed WT group increased significantly in 1 week of cold exposure and rose gradually to 168+/-7 mm Hg by week 5, whereas the BP of the Agt-KO group did not increase until week 3. The cold-induced increase in BP (DeltaBP) was decreased significantly in the Agt-KO mice (19+/-3 mm Hg) compared with that of the WT mice (61+/-5 mm Hg) by 5 weeks of exposure to cold. Both WT and Agt-KO groups had cardiac hypertrophy in cold to the same extent. Agt-KO caused a significant increase in nitric oxide (NO) production. Thus, the RAS may inhibit NO formation. Chronic cold exposure decreased NO production, which may be mediated partially by activation of the RAS. These results strongly support that the RAS plays a critical role in the development of cold-induced hypertension but not cardiac hypertrophy. Moreover, the role of the RAS in cold-induced hypertension may be mediated in part by its inhibition on NO production. The findings also reveal the possible relation between the RAS and NO in cardiovascular regulation.

Topics: Angiotensinogen; Animals; Blood Pressure; Body Weight; Brain; Cold Temperature; Female; Gene Expression; Genotype; Hypertension; Hypothalamus; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Nitrates; Nitrites; Norepinephrine; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Renin-angiotensin-aldosterone system component genes have been associated to essential hypertension. Thus, we studied the association of singe locus or multilocus interactions with young-onset essential hypertension.. This is a case-control study based on a population sample of adolescent at an inner city.. We studied 54 adolescents with hypertension and 121 age-matched normotensives, recruited from a high-school student population of 934 interviewed individuals.. Resting blood pressure was measured on three different days and normalized (Z-score) by sex and age. Genotypes of ACE (I/D) angiotensinogen (T174M and M235T), ATIR (A1166C), and CYP11B2 (C-344T) were determined by PCR/RFLP or ASO.. Although genotype frequencies were not different in both groups, we found a significant dominant effect of ACE D and angiotensinogen 235T alleles on normalized systolic arterial blood pressure in males. This effect was confirmed by sib-pair linkage analysis taking normalized blood pressure as a quantitative trait. We independently analyzed multilocus interactions in normotensive and hypertensive adolescents searching for multiple locus deviation from Hardy-Weinberg or linkage equilibrium. We found that from 63 multilocus combinations, 4 deviated significantly from equilibrium in hypertensive adolescents but none in the normotensives. Deviations from equilibrium may indicate that the combination of alleles at different loci affects susceptibility or resistance to the disease.. In addition to the angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) gene variants, gene-gene interactions may be important causative factors in a complex disease such as young-onset essential hypertension.

Topics: Adolescent; Angiotensinogen; Case-Control Studies; Chromosome Mapping; Female; Gene Frequency; Humans; Hypertension; Linear Models; Male; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Thyrotropin-Releasing Hormone; Renin-Angiotensin System

This study was performed to examine whether there is an inappropriate regulation of intrarenal angiotensinogen in Dahl-salt sensitive rats (DS) fed a high salt diet (HS). Dahl salt-resistant rats (DR) and DS were maintained on HS (8% NaCl) or low salt diet (LS, 0.3% NaCl) for 4 weeks. Systolic blood pressure (SBP), measured by tail-cuff plethysmography, was unaltered in DR (DR+HS, 127+/-3 mm Hg, n=5; DR+LS, 126+/-3, n=5); however, SBP was significantly increased in DS+HS (208+/-7, n=9) compared with DS+LS (134+/-2, n=5). HS suppressed plasma renin activity in both strains (0.7+/-0.2 ng of angiotensin I/mL per hour in DS+HS, 3.1+/-0.5 in DS+LS, 0.8+/-0.2 in DR+HS, 5.1+/-0.7 in DR+LS). Plasma angiotensinogen levels, measured by Western blot analysis, were also suppressed by HS in both strains (36 919+/-2170 integrated densitometric unit in DS+HS, 53 028+/-2752 in DS+LS, 44 722+/-1721 in DR+HS, 55782+/-3785 in DR+LS). However, kidney angiotensinogen levels were significantly increased in DS+HS (75 850+/-4171, integrated densitometric unit) compared with DS+LS (47 232+/-3470), DR+HS (44 748+/-8236), and DR+LS (42 504+/-4052). Urinary excretion of angiotensinogen, measured by radioimmunoassay of angiotensin I after incubation with excess renin, had a similar profile. Urinary excretion of angiotensinogen was significantly increased in DS+HS (2958+/-531 pmol/d) compared with DS+LS (56+/-4), DR+HS (31+/-12), and DR+LS (21+/-7). These data indicate that intrarenal angiotensinogen is enhanced in DS+HS, which is reflected by the increased urinary excretion of angiotensinogen. The results suggest that DS on HS have an inappropriate augmentation of intrarenal angiotensinogen, which may contribute to impaired sodium excretion during a high salt diet and the development of hypertension in this strain.

Topics: Angiotensinogen; Animals; Blood Pressure; Blotting, Western; Hypertension; Kidney; Kinetics; Male; Proteinuria; Rats; Rats, Inbred Dahl; Renin; Sodium Chloride; Urine

The angiotensinogen (AGT) gene polymorphism M235T (a methionine to threonine amino acid substitution) has been investigated in association with essential hypertension (EHT) based on conventional measurement of blood pressure (BP); however, the results have been inconsistent. Recently, we have been conducting lines of genetic analysis on a general population of Ohasama Town in Iwate Prefecture, Japan, who measured their BP at home (Ohasama genetic analysis and home BP project). We here assessed the association between AGT M235T polymorphism and hypertension within the same population (1,245 subjects aged 40 years and over). AGT M235T polymorphism was determined by genotyping the AGT T+31C polymorphism, which has complete disequilibrium with the AGT M235T polymorphism. We defined subjects as hypertensive if they were being treated with antihypertensive medication and/or had home BP values of more than 135 mmHg in systole and/or 85 mmHg in diastole. The genotype frequencies were similar to those in previous Japanese studies. There was no significant difference among the genotypes in home BP values (p = 0.63/0.74 for systolic/diastolic blood pressure) or in prevalence of hypertension (MM: 44.7%; MT: 42.3%; TT: 39.6%; p = 0.61). No difference was noted in the frequency of familial history of hypertension. Pulse pressure, however, was significantly different among the genotypes (p = 0.049), and this association was prominent in the older (age260) population (p = 0.0018), but not noted in the younger population (60 > age > or = 40). In conclusion, the present analysis confirmed the lack of a significant effect of AGT M235T polymorphism on blood pressure level, but the difference in pulse pressure in the older population suggests that further investigations of this polymorphism should be made in the Japanese population.

Topics: Aged; Alleles; Amino Acid Substitution; Angiotensinogen; Blood Pressure; Blood Pressure Determination; Female; Genotype; Humans; Hypertension; Japan; Male; Middle Aged; Polymorphism, Genetic

Polymorphism of the promoter region of the angiotensinogen gene (ATG) and an angiotensin I-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism were studied in three different groups of Kazakhs (control group, patients with cardiovascular disease (CAD) and patients with arterial hypertension (AH)) using three methods. A comparative analysis of the distribution of genotype and allele frequencies was conducted.

Topics: Angiotensinogen; Asian People; Ethnicity; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Introns; Kazakhstan; Male; Middle Aged; Myocardial Ischemia; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Promoter Regions, Genetic; Sequence Deletion

The genes of the renin-angiotensin system have been subjected to intense molecular scrutiny in cardiovascular disease studies, but their contribution to risk is still uncertain. In this study, we sampled 192 African American and 153 European American families (602 and 608 individuals, respectively) to evaluate the contribution of variations in genes that encode renin-angiotensin system components of susceptibility to hypertension. We genotyped 25 single-nucleotide polymorphisms in the renin-angiotensin system genes ACE, AGT, AGTR1, and REN. The family-based transmission/disequilibrium test was performed with each single-nucleotide polymorphism and with the multilocus haplotypes. Two individual single-nucleotide polymorphisms were significantly associated with hypertension among African Americans, and this result persisted when both groups were combined. The associations were confirmed in haplotype analysis for REN, AGTR1, and ACE in African Americans. Consistent but less significant evidence was found in European Americans. We also randomly sampled unrelated individuals across families to obtain 84 cases and 108 controls among the African Americans and 41 cases and 113 controls in the European Americans. Single-nucleotide polymorphism and haplotype analyses again showed consistent, albeit weaker, results. Thus, in this biracial population sample, we find evidence that interindividual variation in the renin-angiotensin system genes contributes to hypertension risk.

Topics: Adult; Angiotensinogen; Black People; Blood Pressure; Case-Control Studies; Female; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin; Renin-Angiotensin System; White People

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid found in beef, lamb, and dairy products. CLA has attracted considerable attention over the past several decades because of its potentially beneficial biological effects, including protective effects against several cancers, atherosclerosis, and obesity. Here we provide the first evidence that the 10trans,12cis-CLA isomer is able to suppress increases in blood pressure during the onset of obesity in OLETF rats. After 3 weeks of feeding with 10t,12c-CLA, systolic blood pressure was significantly lowered compared with rats fed linoleic acid or 9c,11t-CLA. Abdominal adipose tissue weight was also significantly lowered in rats fed 10t,12c-CLA, but not in those which were fed 9c,11t-CLA. In addition, we found that the relative mRNA expressions of angiotensinogen and leptin were suppressed by 10t,12c-CLA in adipose tissue. We speculate that the antihypertensive effect of 10t,12c-CLA can be attributed to the lowered secretion of hypertensive adipocytokines from abdominal adipose tissues.

Topics: Adipose Tissue; Angiotensinogen; Animals; Base Sequence; Dietary Fats, Unsaturated; Hypertension; Leptin; Linoleic Acid; Male; Obesity; Rats; Rats, Inbred OLETF; RNA, Messenger; Stereoisomerism

Over the past 20 years, the interest of the scientific community was increasingly placed in the field of genetic epidemiology and molecular genetics of blood pressure control. This paper explores references related to essential hypertension, gene and genetic epidemiology indexed in the MedLine health science database during the period 1980-2001. A systematic literature search was performed using selected keywords, such as 'genetic', 'genome' or a combination of words. We considered the study heading and evaluated the time profile of published articles. A total number of 3116 publications was collected and analyzed. Allelic distribution for the most studied polymorphisms of the renin-angiotensin system in different world populations was reviewed and reported together with a detection of their frequency in Italy: essential hypertensive patients (n = 90), healthy unrelated subjects (n = 300). Molecular variants at angiotensinogen (M and T), angiotensin II type 1 receptor (A and C) and angiotensin-converting enzyme (D and I) genes were analyzed by amplified fragment length polymorphism. A significant association was detected by chi2 analysis for angiotensinogen and angiotensin II-type I receptor allele distribution in hypertensive patients, in accordance with previous reports. Genetic data and methods are contributing more and more to epidemiological studies of complex diseases, and their application is influenced by information availability and Genome Project results.

Topics: Amplified Fragment Length Polymorphism Analysis; Angiotensinogen; Humans; Hypertension; Polymorphism, Genetic; Renin-Angiotensin System

The aim of this study was to assess the association of the angiotensinogen M235T polymorphism with arterial blood pressure (BP) at rest and under physical stress in a homogeneous large-scale study population. In all, 1903 men who passed routine medical examination for military flying duty were recruited. BP and heart rate were measured at rest, during, and after bicycle ergometry. Genotyping for the AGT M235T polymorphism was carried out by PCR and RFLP technique. The AGT T235 allele was associated with a significantly higher diastolic BP (n=1903; MM 81+/-8, MT 83+/-7, TT 83+/-8; P=0.003). Pulse pressure (PP) at rest differed significantly between AGT genotypes (n=1903; MM 51+/-10 mmHg, MT 49+/-10 mmHg, TT 49+/-10 mmHg; P=0.001). During physical activity, BP values showed no significant difference between genotypes. In healthy young men, the AGT T235 allele is significantly associated with elevated diastolic BP but also reduced PP at rest. During physical activity, the AGT polymorphism had no impact on blood pressure, indicating the existence of other counteracting mechanisms, which might balance the influence of this gene.

Topics: Adult; Angiotensinogen; Blood Pressure; Diastole; Exercise Test; Genotype; Germany; Heart Rate; Humans; Hypertension; Male; Polymorphism, Genetic; Rest; Systole; White People

Gene encoding components of the renin angiotensin system (RAS) have been implicated with the increased risk of cardiovascular disease (CVD). Two variants of the angiotensinogen (AGT) gene, M235T and T174M, have been shown to be associated with increased risk of hypertension. In the present study, we examined the association of these two polymorphisms and their synergistic interaction with the angiotensin I-converting enzyme (ACE) deletion homozygote genotype (D/D) on subjects with coronary heart disease (CHD) and hypertension. We studied 131 healthy individuals, 141 angiographically verified CHD patients, and 159 hypertensive subjects. The identification of the ACE and AGT gene polymorphisms was carried out using a PCR-based restriction endonuclease digestion method. There was no significant difference in the distribution of the M235T and T174M variants between the two test groups and the control group. Association was also not seen when analysis was carried out in patients when subgrouped according to the extent of the severity of the disease. In addition, the risk was not restricted to subjects carrying the D allele of the ACE gene and T235T of AGT. M235T and T174M variants do not contribute to the increased risk of CHD or hypertension in the Indian population.

Topics: Adult; Angiotensinogen; Apolipoproteins B; Blotting, Southern; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Data Interpretation, Statistical; DNA; fas Receptor; Female; Gene Frequency; Genotype; Humans; Hypertension; India; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Triglycerides

To clarify the interactive effects of alcohol intake and angiotensinogen gene codon 174 (T174M) polymorphisms on blood pressure in Japanese male workers. On the basis of data from health examinations, nutrition survey and T174M genotype analysis conducted for 185 Japanese male workers at 2000, the prevalence of high-normal blood pressure (HNBP) and hypertension were compared between the four subgroups crossed by two T174M genotype categories ('TT' type, and 'TM or MM' type) and two alcohol intake categories (less than 13.7 g per day, and 13.7 g or more per day). Furthermore, for 95 subjects who had been normotensive at 1998 among them, risk of development into HNBP or hypertension at 2000 were compared across the four subgroups. The findings showed that the HNBP prevalence adjusted for age, body mass index, smoking habits and sodium intake in 2000 was significantly (p=0.03) greater in 'TM or MM' type (57.9%) than in 'TT' type (24.9%) in subjects with 13.7 g or more of daily alcohol intake, whereas no difference in this parameter was found between the two genotypes in those with less than 13.7 g of daily alcohol intake (18.2% and 18.3%, respectively). The risk for development into HNBP at 2000 was also greatest in 'TM or MM' type with 13.7 g or more of daily alcohol intake among the four subgroups, although there were not significant differences between the four subgroups. The prevalence of hypertension or development risk for hypertension did not significantly differ between the four subgroups. Therefore, it can be seen that alcohol drinking might be specifically associated with the HNBP in M allele carriers of angiotensinogen gene T174M polymorphism.

Topics: Alcohol Drinking; Alleles; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Body Mass Index; Cross-Sectional Studies; Genotype; Heterozygote; Humans; Hypertension; Japan; Longitudinal Studies; Male; Middle Aged; Polymorphism, Genetic; Prevalence; Reference Values; Risk Assessment

Autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease, is characterized by the development of hypertension and end stage renal disease. An increase in the activity of the renin-angiotensin system, due to a renal ischemia caused by cyst expansion, contributes to the development of hypertension and renal failure in ADPKD. Recently, the angiotensinogen (AGT) gene, M235T, and angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with the susceptibility to develop hypertension and renal disease. We hypothesized that the AGT M235T and ATR A1166C polymorphisms could account for some of the variability in the progression of ADPKD. Genotyping was performed in 108 adult patients with ADPKD, and 105 normotensive healthy controls, using PCR and restriction digestion. We analyzed the effects of the AGT M235T and ATR A1166C polymorphisms on hypertension and age at the end stage renal disease (ESRD). Of the 108 patients with ADPKD, 64 (59%) had hypertension and 24 (22%) reached the ESRD. The prevalence of hypertension were; [MM+MT], [TT] genotypes, 60%, 59% (p=1.00); [AA], [AC+CC] genotypes, 60%, 50% respectively (p=0.54). The ages at the onset of ESRD were; [MM+MT], [TT] genotypes, 50 +/- 9 years, 56 +/- 8 years (p=0.07); [AA], [AC+CC] genotypes, 54 +/- 8 years, 52 +/- 14 years, respectively (p=0.07). There were no differences in the prevalence of hypertension and the ages at the ESRD in relation to the AGT M235T and ATR A1166C polymorphisms. We suggest that the AGT and ATR gene polymorphisms would not have an effect on hypertension or the ESRD in ADPKD.

Topics: Adult; Age of Onset; Angiotensinogen; Disease Progression; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Polymorphism, Genetic; Prevalence; Receptor, Angiotensin, Type 1; Receptors, Angiotensin

To evaluate the association of angiotensinogen (AGT) gene with AGT level and hypertension based on the overall genetic variation of the AGT gene in among African-Americans.. All non-rare single nucleotide polymorphisms (SNPs) in AGT were identified by resequencing 24 individuals. Five tagging SNPs were selected based on the pairwised linkage disequilibrium (LD) pattern and were genotyped in 284 individuals. Association studies of AGT level and hypertension were performed using these five tagging SNPs.. No significant association with AGT level or hypertension was found in analyses of each of the five single SNPs. However, one of the haplotypes defined by these five SNPs was significantly associated with AGT level (P = 0.046), although this haplotype was not associated with hypertension.. Identification of genetic polymorphisms associated with risk of hypertension has been frustratingly difficult. Two strategies adopted to improve precision are the use of intermediate phenotypes and summarization of genetic information using haplotypes. These strategies appeared to yield a modest increase in precision at the AGT locus with respect to the physiological intermediate, but did not lead to significant association of the molecular markers with hypertension. Additional research is required to increase confidence in haplotype mapping as an epidemiological analysis tool.

Topics: Adult; Angiotensinogen; Black or African American; Body Mass Index; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Risk Factors

Enhanced efficiency of the reaction between transgenic Ren-2 mouse renin and endogenous rat angiotensinogen has been suggested as 1 mechanism that contributes to the accelerated hypertension and increased tissue angiotensin of the (mRen-2)27 transgenic rat. This was tested in a study conducted at pH 7.4 in vitro that compared the kinetic constants of purified mouse Ren-2 and rat renin (each at 100, 75, 50, and 25 pmol/L) reacting with physiologic concentrations of rat angiotensinogen (0 to 4 micromol/L). Under these conditions, the kinetic constants for Ren-2 (Km, 1.8 micromol/L; Kcat, 0.07/s; and Kcat/Km, 0.04 L x micromol(-1) x s(-1)) were not different from rat renin. However, Ren-2 renin acting on its homologous mouse angiotensinogen was confirmed as being much slower. We conclude that hypertension in the Ren-2 rat is not related to renin kinetics. Other mechanisms are considered, with reference to human essential hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Disease Models, Animal; Hypertension; Kinetics; Male; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Renin; Species Specificity

We sought to determine whether genes of the renin-angiotensin-aldosterone system can predict the nonmodulating intermediate phenotype in essential hypertension. Aldosterone responses to angiotensin II were assessed in 298 subjects with hypertension. Subjects were genotyped at the angiotensinogen M235T, angiotensin-converting enzyme I/D, aldosterone synthase C-344 T, renin, angiotensin II type 1 receptor, and adducin loci. The data were analyzed by Student t test, ANOVA, stepwise linear regression and general linear model or GENMOD regression techniques, and chi2 analysis odds ratios (ORs). Aldosterone response varied by genotype for angiotensin and aldosterone synthase but not for the other loci. The combination of angiotensinogen 235 TT and angiotensin-converting enzyme DD showed further reduction (P=0.0377) when compared with angiotensinogen 235 TT alone, an example of genetic epistasis. When the subject was required also to possess the CYP11B2 -344 TT genotype, there was a further substantial reduction. Of these 3 loci, only angiotensinogen 235 TT significantly increased the OR of predicting the nonmodulating hypertensive phenotype (OR, 2.00; 95% confidence interval, 1.152 to 3.51). However, when angiotensin-converting enzyme DD was combined with angiotensinogen 235 TT, the OR nearly doubled to 3.74, with a further increase to 5.36-fold when the subject possessed all 3 genotypes. Thus, the angiotensinogen, angiotensin-converting enzyme, and aldosterone synthase genotypes identified individuals with the nonmodulating phenotype with an increasing degree of fidelity. For this subclass of essential hypertension, it is likely that genotyping can be substituted for complex phenotyping for therapeutic and preventive decision making.

Topics: Age Factors; Aldosterone; Angiotensin II; Angiotensinogen; Epistasis, Genetic; Family Health; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Quantitative Trait Loci; Renin-Angiotensin System; Sex Factors

Polymorphisms of the angiotensinogen (AGT) gene, especially in the promoter region, are in linkage concordance and are associated with hypertension. In this study, we examined the role of AGT promoter polymorphisms, including G-217A, A-6G and M235T variants, and their promoter function in essential hypertension in Taiwanese populations.. An association study was conducted to assess the genotype distribution between hypertensive patients and normotensive subjects. We also used a transient transfection assay to examine basal transcriptional activity of G-217A and A-6G variants in a mammalian cell system.. Hypertensive subjects (390) and normotensive controls (388) of Taiwanese ethnicity were genotyped for the AGT G-217A, A-6G and M235T variants. Promoter activity was studied by cloning the promoter region (-614 to +41 bp) of AGT into the pSEAP2-Basic reporter vector and performing a transient transfection assay in HuH7 and HepG2 cells.. The G-217A variant of the AGT gene was significantly associated with hypertension (P = 0.0047), but the A-6G and M235T polymorphisms were not (P = 0.17 and P = 0.33, respectively). Furthermore, the recessive model of homozygous genotype (-217AA) conferred a high risk for hypertension (odds ratio 3.64) in this population. The -217A variant expressed higher transcriptional activity than -217G in vitro.. Our study showed a significant association between the -217A variant of the AGT gene and hypertension. This variant plays a functional role in basal transcription of AGT, and may confer a risk for hypertension in Taiwanese populations.

Topics: Adenine; Angiotensinogen; Asian People; Genetic Variation; Guanine; Humans; Hypertension; Taiwan; Transcription, Genetic

To investigate the relationship between angiotensinogen (AGT) gene polymorphism and hypertension in type 2 diabetic patients.. A total of 240 patients with type 2 diabetes mellitus were divided into normotensive and hypertensive groups according to their blood pressure measurement, and their fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein and very-low-density lipoprotein were measured. The AGT genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).. The distributions of AGT genotypes in normotensive and hypertensive groups were similar, and the frequency of M allele in female hypertensive patients was significantly higher than that in female normotensive patients.. The M allele of AGT gene is probably related to hypertension in female type 2 diabetic patients.

Topics: Adult; Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment.. We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, -20A-->C), and aldosterone synthase (CYP11B2)(-344C-->T) genes.. The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the -344C allele (n = 75), patients who were homozygous for the -344T allele (n = 156) had both higher ambulatory SBP (150 +/- 1 v 144 +/- 1 mm Hg, P =.002 before and P =.01 after adjusting for multiple genotyping) and office SBP (163 +/- 2 v 156 +/- 2 mm Hg, P =.01 before and P =.05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP.. A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.

Topics: Angiotensinogen; Black People; Blood Pressure Monitoring, Ambulatory; Cytochrome P-450 CYP11B2; Female; Humans; Hypertension; Male; Middle Aged; Outpatients; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Severity of Illness Index; South Africa

The ThrThr genotype of the angiotensinogen (AGT) Met235Thr polymorphism has been associated with elevated AGT levels, hypertension, increased heart disease risk, and improved blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitors. We hypothesized that risk of stroke or myocardial infarction (MI) associated with ACE inhibitor use varies by AGT genotype, with a larger protective effect of ACE inhibitors in individuals with the ThrThr genotype than individuals who are carriers of the Met allele.. We conducted a population-based case-control study. Participants were health maintenance organization members aged 30 to 79 years with treated hypertension. Those who survived incident stroke (n = 116) or MI (n = 208) during the study period were designated as cases. Control subjects (n = 717) were randomly sampled and frequency-matched to MI cases on age, sex, and calendar year. Health history, medication use, and AGT genotype were assessed.. ThrThr genotype was present in 21% of stroke cases, 26% of MI cases, and 19% of control subjects. Compared with nonuse, ACE inhibitor use was associated with lower stroke risk among Thr homozygotes (odds ratio [OR] = 0.37, 95% CI = 0.14 to 0.99) than among Met carriers (OR = 1.4, 95% CI = 0.88 to 2.4; P for interaction =.02). Compared with nonuse, ACE inhibitor use was associated with similar MI risk among Thr homozygotes (OR = 0.90, 95% CI = 0.62 to 1.3) and among Met carriers (OR = 1.2, 95% CI = 0.60 to 2.5; P for interaction = 0.5).. In this hypertensive population, the association of ACE inhibitor use with risk of nonfatal stroke varied by genotype. The protective association between ACE inhibitor use and nonfatal stroke risk among individuals with ThrThr genotype was not observed for nonfatal MI.

Topics: Adult; Aged; Alleles; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Case-Control Studies; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Risk; Stroke

Topics: Angiotensinogen; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System

This study is to explore the association between M235T allele polymorphism of angiotensinogen (AGT) gene and cytokines using essential hypertension probands research method. In hypertensives and controls, polymerase chain reaction combined with restriction endonuclease digestion was used to detect the target genotype variation, and enzyme-lined immunosorbant assay (ELISA) was used to detect the cytokine concentrations (IL-1, IL-6, TNF). The results showed that in hypertensives AGT gene, TT genotype was 55.88%, MT 35.29% and MM 8.82%. The ratio of T/M allele frequency was 0.735/0.265. In controls AGT gene, TT genotype was 47.46%, MT 42.37% and MM 10.17%. The ratio of T/M allele frequency was 0.686/0.314. AGT gene 235 T allele frequency in hypertensives was slightly higher than those in controls. Furthermore AGT gene 235 TT genotype and T allele frequency in middle and high grade of hypertensives were significantly higher than those in mild grade. In subjects of AGT 235 T allele group, the concentrations of IL-1, IL-6 and TNF in hypertensives were significantly higher than those in controls. In subjects of AGT gene 235 M allele frequency, the concentrations of IL-1 and IL-6 in hypertensives were no significant than those in controls. No matter in groups more than 60 years old or less than 60 years old, the concentrations of IL-1, IL-6 and TNF in hypertensives were higher than those in controls. No matter in hypertensives or controls, there were no differences in concentrations of IL-1, IL-6 and TNF when comparing groups more than 60 years old with groups less than 60 years old. The study indicated that AGT gene TT genotype and AGT gene 235 T allele frequency may be an important risk factor for hypertension. The high frequency of AGT gene 235 T allele and the high concentrations of IL-1, IL-6 and TNF in hypertensives may cause hypertension developing. It is also suggested the cytokines may effect the transcription and expression of AGT gene 235 TT genotype in hypertension. The concentrations of IL-1, IL-6 and TNF had nothing to do with age no matter hypertensives or controls.

Topics: Adult; Aged; Alleles; Angiotensinogen; Cytokines; DNA; Enzyme-Linked Immunosorbent Assay; Female; Gene Frequency; Genotype; Humans; Hypertension; Interleukin-1; Interleukin-6; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Tumor Necrosis Factor-alpha

Essential hypertension is a multifactorial disease in which genetic and enviromental factors play an important role. These factors differ in each population. As there are no existing data for the Turkish population, we investigated four Renin Angiotensin System (RAS) gene polymorphisms, the angiotensin converting enzyme (ACE), angiotensinogen (AGN) M235T/T174M and angiotensin II type 1 receptor A1166C polymorphism in 109 hypertensive and 86 normotensive Turkish subjects. Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP), and agarose gel electrophoresis tecniques were used to determine these polymorphism. The frequencies of person that carry ACE D allel (DD+ID) was significantly higher in hypertensive group (99.1%) than controls (80%) (P 0.000). M235T TT genotype was also found significantly higher in hypertensives than control group (20% vs 2.7%; P 0.001). The frequency of AGN 174M allele was higher in the hypertensive group than control subjects (8.76% vs 4.81%). Frequency of ATR1 C allele (AC+CC genotypes) was found higher hypertensives than controls (39.4% vs 25.9%; P = 0.054). Our results suggest that an interaction exists between the RAS genes and hypertension in Turkish population.

Topics: Angiotensinogen; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Turkey

This study investigates the association between the allelic distribution of two polymorphisms of the angiotensinogen (AGT) gene (T174M and M235T in the polypeptide chain) and blood pressure (BP) in a Mediterranean population in the south-west of Europe. The sample consists of 1322 participants from urban and rural areas, from the province of Albacete (218,462 inhabitants), located in the south-east of Spain. The subsample of this study, adjusted by age (over 18 years old) and sex, consists of 401 individuals. A case-control study is conducted which analyses 205 individuals from the group with the highest BP (fifth quintile) and 196 from the group with the lowest BP (first quintile). In addition, a comparative and associated analysis of these polymorphisms with BP level and family history of hypertension is carried out. The T174 allele proved to be more common in the fifth quintile group, although not statistically so. When the presence of threonine was analysed in both polymorphism positions (174 and 235), the TTTT genotype was found to be more common in the fifth quintile than in the first quintile. Moreover, the TTTT genotype was significantly more common in individuals with a family history of hypertension, indicating that it could be considered a predisposing factor to high BP in individuals from such families. In addition, the T174M-T235T genotype was more common in the first quintile group, and showed significant association (P=0.05) with the group that had no family history of hypertension.

Topics: Adult; Aged; Angiotensinogen; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Threonine

We assessed the association between several polymorphisms of angiotensinogen gene (AGT) and essential hypertension using ambulatory blood pressure (BP).. We recruited 802 subjects in a rural Japanese community who were aged >40 years and who gave written informed consent for monitoring of their ambulatory BP and genetic analysis (the Ohasama Study). As a polymorphism of AGT, T+31C, which is in complete linkage disequilibrium with M235T, was determined using the TaqMan polymerase chain reaction method.. The genotype distribution of AGT/T-+31C in the Ohasama Study was similar to that in another large Japanese population. Although there was no significant difference in 24-h and daytime ambulatory BP values, the nighttime BP was significantly lower in the subjects with TT, resulting in greater decline of nocturnal systolic (P = .090) and diastolic (P = .025) BP in subjects with TT.. AGT/T+31C is associated with the circadian BP variation but not with BP level in the Japanese general population.

Topics: Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Japan; Male; Middle Aged; Polymorphism, Genetic; Prevalence

Hypertension is a serious health problem in Western society, in particular for the African-American population. Although previous studies have suggested that the angiotensinogen (AGT) gene locus is involved in human essential hypertension, the molecular mechanisms involved in hypertension in African-Americans remain unknown. We show that an A/G polymorphism at -217 in the promoter of the AGT gene plays a significant role in hypertension in African-Americans. The frequency of the -217A allele was increased significantly in African-American hypertensive subjects compared with normotensive controls. We also show that the nucleotide sequence of this region of the AGT gene promoter bound strongly to CAAT/enhancer-binding protein (C/EBP) family transcription factors when nucleoside A was present at -217. In addition, we show that reporter constructs containing the human AGT gene promoter with nucleoside A at -217 had increased basal transcriptional activity upon transient transfection in HepG2 cells compared with reporter constructs with nucleoside G at -217. Finally, we show that interleukin-6 treatment in the presence or absence of overexpressed C/EBPbeta increased the promoter activities of reporter constructs containing nucleoside A at -217 compared with reporter constructs containing nucleoside G at -217. Because the AGT gene is expressed primarily in liver and adipose tissue, and C/EBP family transcription factors play an important role in gene expression in these tissues, we propose that increased transcriptional activity of the -217A allele of the human AGT gene is associated with hypertension in African-Americans.

Topics: Adult; Aged; Angiotensinogen; Black People; Cell Line; Female; Genes, Reporter; Humans; Hypertension; Male; Middle Aged; Oligonucleotides; Plasmids; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Binding; Transfection; United States

The objective of the study was to analyze the relationship of polymorphisms of the angiotensinogen gene with changes in body weight during 3 y of antihypertensive treatment, in a group of young adults with essential hypertension.. Essential hypertensives, less than 50 y old, never previously treated with antihypertensive drugs and in the absence of diabetes mellitus were included. After the initial evaluation, patients were treated using only non-pharmacological measures (n=29), beta-blockers (n=40) or angiotensin-converting enzyme inhibitors (n=66). Resting blood pressure, biochemical profile and body weight at the beginning and yearly were measured. The polymorphism A-6G of the angiotensinogen gene located in the promoter region was analyzed.. One-hundred and thirty-five patients were included. Genotypes of the A-6G polymorphism of the AGT gene were in Hardy-Weinberg equilibrium (AA 34, AG 63, GG 38). No significant differences were observed among genotypes in terms of age, body mass index, body weight, systolic or diastolic blood pressure. No significant differences in the genotype distribution or in the allele frequencies were observed, although the A allele was most frequent among the obese subjects. During the 3 y of antihypertensive treatment, there was a trend to increase weight despite the dietary recommendations. The slopes of body weight over time, adjusted by age and baseline BMI, differed significantly among the homozygote genotypes (P=0.006). The highest were for those with the AA genotype and the lowest for the GG genotype (1.180+/-0.25 and -0.128+/-0.24 kg/y; P=0.0001). The influence of the genotype in the changes on body weight remained significant after considering its interaction with the kind of antihypertensive treatment, although among subjects carrying the AA genotype those treated with ACEi showed the least body weight change. Furthermore, A-6G genotypes had the largest influence on weight changes, accounting for 19% of the variance, when age, sex and initial body mass index were included in the model.. In a group of young adult hypertensive subjects, there was a trend to increase weight despite dietary recommendations. Subjects with the AA genotype were those with the largest weight gain, but this effect was modified by the antihypertensive treatment.

Topics: Adrenergic beta-Antagonists; Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Body Mass Index; Body Weight; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Time Factors

To explore the role genetic factor plays in the pathogenes is of essential hypertension (EH) among Tibetans and to investigate whether angiotensinogen (AGT) is involved in the pathogenesis of EH.. A case-control association study was conducted among 353 essential hypertensive subjects and 317 genealogic structure-matched normotensive controls, all of Tibetan nationality. The correlation between polymorphism of M235T and 6A-->G variant in AGT gene and EH susceptibility in Tibetans was examined by polymerase chain reaction ( PCR) and PCR/RFLP (restriction fragment lengths polymorphism) with AspI and BstN I,respectively.. (1) The affection rate of EH among the first-degree relatives of Tibetan EH proband was 43.3%. The heritability of EH was 77.2% +/- 13.3% by Falconer method. (2) The plasma rennin activity and angiotensin II (AngII) level among the EH patients were (1.95 +/- 0.11) microgram .L(-1).h(-1) and (72.6 +/- 4.6) ng/L, all significantly higher than those in the controls [(1. 59 +/- 0.11) microgram .L(-1).h(-1) and (51.7 +/- 4.6) ng/L, all P < 0.05].(3) The -6G allele frequency in the promoter of AGT gene was higher in EH group than in the control group (0.36 vs 0.27, kappa(2) = 9.35, P < 0.01). There was a weak association between -6A -->G variant and the plasma AngII level, and there was no significant difference in the genotype distribution and allele frequency of M235T variant between the hypertensive and normotensive groups (P > 0.05).. Genetic factor plays an important role in the pathogenesis of essential hypertension and angiotensinogen gene might be one of the most key susceptibility genes for essential hypertension in Tibetan.

Topics: Adult; Aged; Angiotensinogen; Case-Control Studies; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Tibet

This study examined vascular function and the role of superoxide in mice that chronically express human renin (R+) and human angiotensinogen (A+). Responses of aortas from R+/A+ mice and from their normotensive littermates (RA- mice) were examined in vitro. Endothelium-dependent relaxation to acetylcholine was impaired in vessels from R+/A+ mice (e.g., maximal relaxation to 100 microM acetylcholine was 45 +/- 5% and 65 +/- 3% in R+/A+ and RA- mice, respectively; P < 0.05). Relaxation was also impaired to the endothelium-independent dilators authentic nitric oxide and nitroprusside in vessels from R+/A+ mice. Maximal vasorelaxation to the endothelium-independent, non-nitric oxide dilator papaverine was similar in R+/A+ and RA- mice. Incubation of vessels from R+/A+ mice with Tiron (1 mM), a superoxide scavenger, improved relaxation to acetylcholine, nitric oxide, and nitroprusside. In contrast, incubation with diethyldithiocarbamate (1 mM), an inhibitor of copper-containing SODs, reduced acetylcholine- and nitroprusside-induced relaxation in vessels from both R+/A+ and RA- mice. Basal superoxide levels, measured with lucigenin-enhanced chemiluminescence (5 microM lucigenin) and hydroethidine-based fluorescent confocal microscopy, were higher in vessels from R+/A+ mice and were Tiron and polyethylene glycol-SOD sensitive. These results suggest that increased superoxide contributes to impaired nitric oxide-mediated relaxation in this genetic model of chronic angiotensin II-dependent hypertension.

Topics: Acetylcholine; Angiotensinogen; Animals; Aorta; Blood Pressure; Chelating Agents; Ditiocarb; Humans; Hypertension; Luminescent Measurements; Mice; Mice, Transgenic; Nitric Oxide; Papaverine; Reactive Oxygen Species; Renin; Superoxide Dismutase; Superoxides; Vasodilation; Vasodilator Agents

The extent to which genes modify the relationship between risk factors for hypertension and blood pressure (BP) is unclear. As angiotensinogen is expressed in adipose tissue and angiotensinogen (AGT) gene promoter variants influence the production of angiotensinogen, we evaluated the role of AGT gene variants as potential modifiers of body size-BP relations.. Five hundred twenty-one hypertensives of African origin sampled from a group with a high mean body mass index (BMI) had 24-hour ambulatory BP (ABP) measurements determined off therapy and were genotyped for the AGT -6G-->A, -532C-->T, -20A-->C, and 704T-->C (M235T) gene variants. Genotypes were also determined in 547 control subjects of African origin who had a normal clinic BP. The -6A and -532C alleles were concordant with the M235T variant. Although AGT gene variants had no independent effects on either the presence of hypertension or ABP values in hypertensives, the -20A-->C polymorphism had a marked influence on the relation between ambulatory systolic BP and BMI. This relation was present in patients homozygous for the -20A allele (n=399, r=0.23, P<0.0001), but absent in those with at least one copy of the -20C allele (n=122, r=0.01, P=0.89). The M235T polymorphism did not impact on the BMI-BP relation. Specificity of the -20A-->C polymorphism effect on the BMI-BP relation is further indicated by the lack of effect on the systolic BP-age relation.. An AGT gene promoter region variant is an important modifier of the relation between body size and BP. Hence, these data corroborate the notion that genetic modifiers can produce a profound impact on BP-phenotypic relations.

Topics: Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Body Constitution; Body Mass Index; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Obesity; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Risk Factors

Conflicting results on the relationship between M235T polymorphism of angiotensinogen (AGT) gene and diabetic nephropathy are reported in the literature, probably due to the small number of subjects, to different inclusion criteria and the different genotype analysis methods used. The aim of the present study was to set up a fast, cheap and reliable method to allow the genotyping of M235T polymorphism in a large number of subjects.. We developed in our laboratory a new specifically designed PCR-SSCP method for M235T genotyping whose specificity was compared with that of Allele Specific PCR (ASPCR) and Mutagenically Separated PCR (MS-PCR). The exact M235T genotype was estabilished by direct sequencing. The new PCR-SSCP method was then used to genotype a population of 1171 hypertensive, normoalbuminuric type II diabetes mellitus patients. The patients were also genotyped for ACE I/D polymorphism. For comparison a group of hypertensive non diabetic patients (n = 88) were also screened.. The PCR-SSCP method identified the M235T polymorphism with no misinterpretation at variance with ASPCR and MS-PCR methods that showed a preferential amplification of the T allele. The rare Y248C polymorphism of the AGT gene was also detected by PCR-SSCP. In diabetic hypertensive patients the prevalence of TT genotype was higher than in normotensive healthy controls and equivalent to that found in hypertensive non diabetic patients.. The PCR-SSCP method for detection of M235T polymorphism is a powerful and sensitive tool for rapid, cheap and efficient screening of a large number of samples. The results obtained with this method demonstrate an association of the TT genotype of AGT gene with hypertension, both in diabetic and non diabetic patients.

Topics: Adult; Aged; Alleles; Angiotensinogen; Base Sequence; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Testing; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Reproducibility of Results; Sample Size; Sensitivity and Specificity; Time Factors

Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.. We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.. These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Fibrosis; Gene Targeting; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertension; Imidazoles; Mice; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Organ Size; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Ventricular Remodeling

The genetic background of hypertensive crisis is unknown. We examined the association of polymorphisms in genes involved in the renin-angiotensin-aldosterone-system with hypertensive crisis.. Population-based case-control study.. Emergency department at a tertiary care university hospital.. A total of 182 patients with essential hypertension who were admitted to an emergency department for treatment of hypertensive crisis and 182 age- and sex-matched healthy individuals.. None.. Analysis of polymorphisms in genes coding for angiotensinogen (AJT 704T-->C), angiotensin II receptor 1 (AGTR1 1166A-->C), renin (REN 2646G-->A), renin-binding protein (RENBP 61T-->C), alpha-adducin (ADD1 1378G-->T), beta-2-adrenergic receptor (ADRB2 46A-->G, 79C-->G), and angiotensin I converting enzyme (ACE I/D) was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. MAIN RESULTS Among patients, the ACE I/D polymorphism showed a deviation from Hardy-Weinberg equilibrium (p =.01). In controls, all polymorphisms were in the Hardy-Weinberg equilibrium. The frequency of the DD genotype was increased in patients (n = 70, 38.5%) vs. controls (n = 51; 28.0%;p =.03; odds ratio, 1.61; 95% confidence interval, 1.03-2.50), which was due to the DD genotype in 40 male patients (44%) vs. 23 in male controls (25.3%;p =.004; odds ratio, 3.48; 95% confidence interval, 1.47-8.30). There were no differences in genotype distributions among other polymorphisms.. We demonstrate a possible association of the DD genotype with hypertensive crisis in men.

Topics: Angiotensinogen; Calmodulin-Binding Proteins; Carbohydrate Epimerases; Carrier Proteins; Case-Control Studies; Emergencies; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Receptors, Adrenergic, beta-2; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Ovine fetuses exposed to high concentrations of synthetic (dexamethasone, D) or naturally occurring glucocorticoids (cortisol, F) in utero during early gestation develop high blood pressure in adulthood. To investigate potential mechanisms involved, we examined the role of the renal renin-angiotensin system (RAS). Ewes were infused with isotonic saline (S, n = 11), D (n = 12, 0.48 mg/h), or F (n = 5, 5 mg/h) for 48 h between d 26 and 28 of gestation (term = 150 d). Ewes carrying twins (S, n = 5; D, n = 6; F, n = 5) were killed at 130 d of gestation. The mRNA levels for angiotensinogen, the AT(1) receptor and AT(2) receptor, were increased in the fetal kidneys after D treatment. Prenatal infusions of F produced similar effects on the AT(1) receptor. Single fetuses (S, n = 6; D, n = 6) were cannulated and infused with angiotensin II for 3 d beginning at 127 d of gestation. Basal blood pressure was similar in both groups and increased similarly with angiotensin II infusion. However, increases in urine flow and glomerular filtration rate were significantly reduced and kidney weights increased in the D-treated group. These results indicate that treatment with D very early in gestation causes significant alterations in the RAS in the fetal kidney 100 d later with functional consequences. Changes in the RAS in the developing kidney may be an important mechanism in the development of adult disease.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Blotting, Western; Dexamethasone; Diuresis; Female; Gestational Age; Glomerular Filtration Rate; Glucocorticoids; Hydrocortisone; Hypertension; Immunohistochemistry; Kidney; Maternal-Fetal Exchange; Nucleic Acid Hybridization; Organ Size; Polymerase Chain Reaction; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Sheep

Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT1) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106+/-5 mm Hg, n=9) compared with the control group (group S; 91+/-3 mm Hg, n=8; P<0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. At 130 days of gestation, dexamethasone administered between 26 to 28 days of gestation (group DF; n=8), resulted in an increased expression of angiotensinogen in hypothalamus (in arbitrary units: 2.5+/-0.3 versus 1.3+/-0.3 in the saline group [group SF], n=10; P<0.05). In addition, there was higher expression of the AT1 receptors in medulla oblongata in group DF (2.6+/-0.6 versus 1.1+/-0.2 in group SF; P<0.01). This effect of prenatal dexamethasone treatment was still evident in females at 7 years of age (group DA; n=5; 2.6+/-0.5 versus 1.1+/-0.2 in group SA; n=6, P<0.05). In conclusion, brief prenatal exposure of the pregnant ewe to dexamethasone leads to hypertension in adult animals of both sexes. Most interestingly, the mechanism leading to programming of hypertension might be linked with the brain angiotensin system.

Topics: Angiotensinogen; Angiotensins; Animals; Blood Pressure; Brain Chemistry; Dexamethasone; Drug Administration Routes; Female; Fetal Weight; Fetus; Gene Expression; Glucocorticoids; Hormone Replacement Therapy; Hypertension; Hypothalamus; Male; Medulla Oblongata; Models, Animal; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Sex Factors; Sheep; Testosterone

Left ventricular hypertrophy in patients with hypertension is a main clinical prognostic entity The aim of this study was to evaluate the association between mutations at genes of the renin-angiotensin system (RAS) and the development of left ventricular hypertrophy. Genetic polymorphism in angiotensinogen (AGT) and angiotensin Il-type 1 receptor (AT1R) genes was examined in a group of well-selected essential hypertensive caucasians with left ventricular involvement (n = 40) and a group of healthy unrelated caucasians (n = 150). Cardiac morphology and function were assessed by M-mode echocardiography. Molecular variants were analysed by amplified fragment length polymorphism. We observed a statistically significant difference both for AGT and AT1R genotype distribution in patients with left ventricular hypertrophy compared with controls (p<0.05). A 0.49 and 0.225 frequency was detected among cases for T and C mutant alleles at AGT and AT1R genes. Mutations in RAS genes are involved in the pathophysiology of target-organ damage in essential hypertension. Evaluation of molecular factors conferring a risk of developing heart involvement may lead to better identification of patient subgroups and more effective control of the clinical course.

Topics: Adult; Aged; Alleles; Angiotensinogen; Female; Heart Function Tests; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Mutation; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System

Predispositions to essential hypertension and cardiovascular diseases are possibly associated with gene polymorphisms of the renin-angiotensin system. Gene polymorphisms of angiotensinogen and angiotensin-converting enzyme genes have been suggested to be risk factors for hypertension and myocardial infarction. Concerning the polymorphism of aldosterone synthase (CYP11B2) gene, earlier studies have shown inconsistent results in terms of its relation to hypertension. In the present case-control study, we investigated the association of -344T/C polymorphism in the promoter region of human CYP11B2 gene with genetic predisposition to hypertension. The genotype of -344T/C polymorphism was determined in essential hypertension subjects (n=250) and normotensive subjects (n=221). The distributions of three genotypes (TT, TC, and CC) were significantly different between the hypertensive and the normotensive groups (chi(2)=9.61, P=0.008). Namely, the frequency of C allele was higher in the hypertensive patients than in the normotensive subjects (34.2 vs 26.5%, P=0.010). Our data suggest that the -344C allele of CYP11B2 gene polymorphism is associated with the genetic predisposition to develop essential hypertension.

Topics: Adult; Angiotensinogen; Cytochrome P-450 CYP11B2; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System

Human hypertension is a complex, multifactorial disease with a heritability of more than 30-50%. A genetic screening test based on analysis of multiple single-nucleotide polymorphisms (SNPs) to assess the likelihood of developing hypertension would be helpful for disease management.. Tailed allele-specific primers were designed to amplify by PCR six biallelic SNP loci [three in G protein-coupled receptor kinase type 4 (GRK4): R65L, A142V, and A486V; two in angiotensinogen: -6G-->A and M235T; and one in aldosterone synthase: -344C-->T] associated with essential hypertension. PCRs of SNP loci were coupled (via a common sequence of 21 nucleotide tails) to incorporate Universal Amplifluor(TM) primers labeled with fluorescein or sulforhodamine in a homogeneous format. Use of Amplifluors in SNP PCRs produced labeled amplicons, the fluorescence of which was quantified by a microplate reader and then analyzed via an Excel macro to provide genotypes for all six SNP loci. Unique restriction endonucleases were identified for five SNP loci that could independently confirm homogeneous PCR results when needed.. We developed six homogeneous PCR assays that were set up, performed, and fluorometrically analyzed in 96-well microplates. Allele frequencies were determined for six SNPs in 60 Italian hypertensive patients and a control group of 60 normotensive persons. A significant correlation (P = 0.034) between one SNP [GRK4 (A486V)] and the hypertensive patients was observed. Genotyping results for five of six SNPs were confirmed by digesting corresponding amplicons with locus-specific restriction endonucleases.. We developed a simple and homogeneous fluorescent protocol that has been used to determine the SNP genotype for six loci in a population of hypertensive and normotensive persons. We also observed a significant association (P = 0.034) between one SNP (A486V) and an Italian population of mildly hypertensive patients.

Topics: Angiotensinogen; Cytochrome P-450 CYP11B2; DNA Primers; Fluorescence Resonance Energy Transfer; Fluorometry; G-Protein-Coupled Receptor Kinase 4; Genotype; Humans; Hypertension; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases

Rats exposed chronically to a cold environment (5 degrees C/4 degrees F) develop hypertension. This cold-induced hypertension (CIH) is a non-genetic, non-pharmacological, non-surgical model of environmentally induced hypertension in rats. The renin-angiotensin system (RAS) appears to play a role in both initiating and/or maintaining the high blood pressure in CIH. The goal of the present study was to evaluate the role of central and peripheral circulating RAS components, angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, in CIH. Seventy-two Sprague-Dawley adult male rats were used. Thirty-six rats were kept in cold room at 5 degrees C while the other 36 were at 24 degrees C as controls for 5 weeks. Systolic blood pressure (SBP) was recorded by tail cuff. The SBP was increased in rats exposed to cold within 1 week, and this increase was significant for the next 2-5 weeks of the cold exposure (p<0.01). Three subgroups of the cold-treated and control rats (n=12) were sacrificed at 1, 3 and 5 weeks. The brain and liver were removed and plasma was saved. The AGT mRNA significantly increased in the hypothalamus and liver in cold-treated rats from the first week of exposure to cold, and was maintained throughout the time of exposure to cold (n=4, p<0.01). The AGT protein levels in the brain, liver and plasma did not differ significantly between cold-treated and control rats (p>0.05, n=4). The hypothalamic Ang II levels were significantly increased, whereas plasma Ang II levels significantly decreased, in the rats of 5 weeks of cold exposure (n=8, p<0.05). Plasma ACE significantly increased in the rats of 1 week of cold exposure (p<0.05, n=12). The results show differential regulation of RAS components, AGT, ACE and Ang II, between brain and periphery in cold-exposed rats. We conclude that the exposure to low temperature initially increases plasma RAS but with continuous exposure to cold, the brain RAS maintains the hypertension, probably by sustained sympathetic activation, which would provide increased metabolism but also vasoconstriction leading to hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Brain; Cold Temperature; Disease Models, Animal; Hypertension; Hypothalamus; Liver; Male; Peptidyl-Dipeptidase A; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Time Factors

There are several controversies concerning the enhanced gene expression of cardiac renin-angiotensin system components in spontaneously hypertensive rats (SHR) compared with their normotensive control Wistar-Kyoto (WKY) rats. We hypothesized that these discrepancies arise from circadian fluctuations in gene expression. We examined the circadian mRNA expression of renin, angiotensinogen, ACE, and angiotensin type 1a (AT1a) and type 2 (AT2) receptors in the hearts of SHR and WKY rats by real-time quantitative reverse transcription-polymerase chain reaction. The cardiac mRNA expression of the renin-angiotensin system components showed circadian oscillations in both SHR and WKY rats. The amplitudes of these circadian fluctuations were greater in the SHR than in the WKY rats. The mRNA levels of the renin-angiotensin system components were also increased in the SHR compared with the WKY rats at many time points (especially during the dark phase). However, the levels of ACE, AT1a receptor, and AT2 receptor mRNA in the SHR and WKY rats were almost the same during the late light phase. In contrast to mRNA expression, ACE activity was similar both at the time of maximum and minimum mRNA expression. The AT1 receptor antagonist candesartan upregulated AT1a receptor mRNA and downregulated ACE mRNA at specific time points only in the SHR group. Our findings of differential diurnal expression of cardiac renin-angiotensin system genes in SHR and WKY rats appear to explain the discrepancies between prior studies. However, the physiological relevance of the differential circadian mRNA expression of the renin-angiotensin system components remains to be elucidated.

Topics: Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Circadian Rhythm; Enzyme Activation; Gene Expression Regulation; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles

To investigate the relationship between the polymorphism of angiotensinogen gene (AGT) and the risk for hypertension in a Chinese population.. Three polymorphisms of AGT gene were analyzed in 335 patients with documented essential hypertension and 196 control subjects by using PCR-restriction fragment length polymorphism. Expectation maximization(EM) algorithm was then used for pairwise linkage disequilibrium test and haplotype analysis of AGT polymorphisms.. Linkage disequilibrium between M235T and A-20C, between M235T and A-6G, between A-20C and A-6G was observed (P<10(-4)). The case-control analysis revealed that the frequency of T235 is significantly higher in essential hypertension patients than in control subjects. But all haplotype frequencies showed no significant difference between the patient and control groups.. No association was noted between the haplotypes of AGT gene and hypertension in tested people, but T235 allele might play an important role in increased risk for essential hypertension.

Topics: Alleles; Angiotensinogen; DNA; Gene Frequency; Genotype; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length

We sought to perform a tree-based analysis of lifestyle risk factors for hypertension in pregnancy (HP) with univariate and multivariate analyses. Seventy-eight HP patients and 199 normal controls were recruited from primiparous women 20 to 34 years of age. Data from angiotensinogen (AGT) genotyping and data from a self-administered questionnaire about lifestyle were subjected to univariate and multivariate analyses. By dividing the subjects into two subgroups--those who possessed "the TT genotype of AGT" and "body mass index (BMI) < 24" and those who did not--we were able to examine the acquired risk factors for HP during pregnancy in these two groups. Multivariate analysis selected "mentally stressful condition" and "no antenatal training during pregnancy" in the former group, and "poorly balanced diet" in the latter group. Determination of factors obvious before pregnancy, such as genotype or prepregnancy BMI, may be useful for devising effective individualized strategies for preventing HP.

Topics: Adult; Angiotensinogen; Body Mass Index; Case-Control Studies; Female; Genetic Markers; Genetic Variation; Genotype; Humans; Hypertension; Multivariate Analysis; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Factors

In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008 %, 2.2 % or 4.4 % sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg(-1) day(-1)) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Enzyme Inhibitors; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Rats; Rats, Inbred WKY; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary

Topics: Adult; Age of Onset; Angiotensinogen; Chromosome Mapping; Chromosomes, Human, Pair 17; Genetic Markers; Humans; Hypertension; Linkage Disequilibrium; Models, Genetic; Nuclear Family; Peptidyl-Dipeptidase A; Renin-Angiotensin System

In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Brain; Chlorides; Desoxycorticosterone; Diuresis; Hypertension; Injections, Intraventricular; Kidney; Male; Mineralocorticoid Receptor Antagonists; Potassium; Rats; Rats, Wistar; Receptors, Mineralocorticoid; RNA, Messenger; Sodium; Sodium Chloride, Dietary; Spironolactone; Time Factors; Transcription, Genetic

The case-control study design, a common staple of epidemiology, is increasingly used to test for genetic association. The simplicity of the design accounts for both its appeal and its limitations. Too often, however, apparent controversy arises for lack of appreciation of basic tenets underlying statistical testing. Power and replication are two concepts most commonly ignored in evaluating such studies. We review the basic principles of statistical testing, recall simple means to calculate power, and provide numerical examples pertaining to the association between angiotensinogen and essential hypertension.

Topics: Alleles; Angiotensinogen; Case-Control Studies; Genetic Linkage; Genotype; Humans; Hypertension; Statistics as Topic

Recent experimental evidence suggests a role for tissue renin-angiotensin systems in the development of hypertension. To test the importance of tissue renin-angiotensin systems in the development and maintenance of angiotensin II-dependent hypertension, we generated a transgenic model in which exon 2 of the human angiotensinogen gene is flanked by loxP sites (hAGT(flox)) so that this region of the gene can be deleted by the cre-recombinase. Double transgenic human renin and hAGT(flox) (R(+)/A(+flox)) mice of two independent lines exhibited elevated blood pressure. Acute administration of an adenovirus containing cre-recombinase (Adcre) lowered blood pressure by 30 mm Hg over a 4-day period as measured with fluid filled catheters. The chronic effect of Adcre administration on blood pressure was determined by radiotelemetry in a separate group of R(+)/A(+flox) mice. Blood pressure decreased by 25 mm Hg from baseline by day 8 post-Adcre, but increased on each day thereafter until it was 90% of baseline by day 21 post-Adcre. Expression analysis indicated the absence of detectable hAGT mRNA in the liver at day 5 post-Adcre, but reappeared at normal levels at days 14 to 21 post-Adcre. These studies suggest that Adcre is effective for acute, but not chronic, elimination of hepatic hAGT. Chronic elimination of hepatic hAGT will likely require the use of transgenic mice endogenously expressing cre-recombinase in the liver.

Topics: Adenoviridae; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Hypertension; Integrases; Mice; Mice, Transgenic; Viral Proteins

(1) Salt sensitive hypertension, which occurs as a result of treatment with nitric oxide synthase inhibitors, is associated with a loss of the usual down-regulatory effect of dietary sodium on angiotensin II (Ang II) synthesis. In the spontaneous hypertensive rat (SHR), which suffers a relative NO deficiency, the hypertension is in part salt sensitive. We sought to determine therefore whether the salt sensitive component to the hypertension was associated with a loss of the regulatory effect of dietary sodium on Ang II synthesis. (2) Male SHR were placed on low, intermediate or high salt diets for 4 weeks and their blood pressure recorded. After 4 weeks, blood was collected for determination of renin, angiotensinogen, Ang I, Ang II and aldosterone concentrations, as well as ACE activity. (3) The increase in systolic blood pressure in rats on the high salt diet was significantly greater than in those on the low (P < 0.005) and intermediate salt diets (P < 0.0005). Plasma renin and aldosterone concentrations and ACE activity decreased with increasing dietary sodium. However, the concentrations of Ang II and angiotensinogen both increased in the rats on the high salt diet (Ang II: P < 0.05; angiotensinogen: P < 0.05). (4) We conclude that the hypertension in the SHR is in part salt sensitive and that this salt sensitive component is associated with a loss of the normal down-regulatory effect of dietary sodium on Ang II and angiotensinogen synthesis.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Hypertension; Losartan; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin; Sodium Chloride, Dietary

Arterial hypertension (HT), secondary to cyclosporine A (CsA) used as main immunosuppressive treatment in renal transplantation (RTx), is very frequent (70%), usually severe and explained mostly by vasoconstriction of the glomerular afferent arteriole with secondary sodium and water retention.. In a retrospective study, we have analyzed 294 consecutive recipients receiving a first renal cadaveric allograft and all treated with CsA (the majority with triple therapy). We studied, by molecular biology, the polymorphism of genes previously implicated in essential HT such as: angiotensin-converting enzyme (ACE: II, ID and DD), angiotensinogen (AGT: MM, MT and TT), angiotensin II type 1 receptor (AT1-R: AA, AC and CC) and endothelial constitutive nitric oxide synthase (ecNOS: aa, ab and bb), and correlated the data to the prevalence and severity of post-Tx HT. This cohort included 195 (66%) males and 99 females with a mean age of 42 years at time of Tx. The presence and severity of post-Tx HT were indicated by initial persistent blood pressure over 140/90 mmHg with the need for at least one anti-hypertensive drug and by the number of anti-HT medications required to achieve its control.. The distribution of the specific alleles and genotypes for ACE, AGT, AT1-R, and ecNOS was not different in transplant recipients compared to 181 controls. At 5 years post-Tx, the prevalence of HT was 72% (169 out of 235) among functioning grafts. There was no significant difference for ACE, AGT, AT1R and ecNOS genotypes distribution between hypertensive vs non-HT recipients. The number of anti-hypertensive drugs prescribed was not different among ACE, AGT, and AT1-R genotypes. However, the a allele and the non-bb genotype (aa + ab) for ecNOS were significantly (p = 0.001) associated with a less severe HT, needing fewer anti-HT drugs. At 10 years post-Tx, the HT prevalence remained high 78% (67 out of 86) among functioning Tx. However, the limited numbers did not allow further correlation.. This study produced mainly negative results except for ecNOS-a allele, which seems to protect against severe hypertension. The explanation remains speculative but probably relates to the known cyclosporine-induced upregulation of ecNOS gene and enzyme activity.

Topics: Adolescent; Adult; Aged; Angiotensinogen; Child; Child, Preschool; Cyclosporine; Female; Genotype; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Retrospective Studies

The renin-angiotensin-aldosterone system (RAAS) plays a well-recognized role in the regulation of BP and in salt and water balance. Since hypertension affects a considerable proportion of obese patients, circulating RAAS has been studied in obese subjects with and without hypertension, albeit with conflicting results. Furthermore, attention has recently focused on the expression of the components of the Renin-angiotensin system (RAS) in some organs, including adipose tissue where it seems to be involved in the regulation of growth and differentiation. The aim of our study was to investigate circulating RAAS and adipose tissue RAS in obese patients with and without hypertension and in matched controls. PRA, and plasma and urinary aldosterone levels were measured in 35 obese, 30 hypertensive obese patients and in 20 controls. In addition, the expression of angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1) genes was studied in sc adipose tissue from 8 obese, 6 hypertensive obese and 6 healthy subjects. As previously demonstrated in other studies, there were no significant differences in the levels of circulating RAAS components in the 3 groups. As regards local RAS, interestingly, we found that AT1 gene was significantly more expressed in sc adipose tissue from obese patients with hypertension than in those without hypertension and controls. By contrast, AGT levels were similar in the 3 groups. Our data do not support the hypothesis of an involvement of circulating RAAS in the development of obesity-related hypertension. On the other hand, local RAS seems to be differently regulated in sc adipose tissue from obese patients with hypertension with respect to normotensive obese patients and controls.

Topics: Adipose Tissue; Adult; Aldosterone; Angiotensinogen; Blood; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Reference Values; Renin; Renin-Angiotensin System; RNA, Messenger

Peptide nucleic acids (PNAs) are uncharged DNA analogs that hybridize to complementary sequences with high affinity and stability. We previously showed that PNAs, after intraperitoneal injection into rats, are effective antisense compounds in vivo. The present study was designed to test whether PNAs also have antigene effects in vivo. The renin-angiotensin system is critical in the control of blood pressure. We designed and synthesized sense (antigene) PNAs to angiotensinogen, which is the precursor protein that leads to angiotensin I and II. Spontaneously hypertensive rats received intraperitoneal injections of either 20 mg/kg sense-angiotensinogen-PNA, mismatch-angiotensinogen PNA, or saline. Only the sense-angiotensinogen PNA treatment resulted in a significant decrease in plasma angiotensin I, systolic blood pressure, and liver and brain angiotensinogen mRNA levels. Thus, these results demonstrate on the molecular, protein, and physiological levels that antigene PNAs are effective in vivo upon systemic administration.

Topics: Analysis of Variance; Angiotensin I; Angiotensinogen; Animals; Blood Pressure; Brain; Gene Targeting; Hypertension; Liver; Male; Peptide Nucleic Acids; Rats; Rats, Inbred SHR; RNA, Messenger

The aim of the study was to assess the existence of possible associations among frequent polymorphisms in angiotensinogen genes and some of the risk factors for essential hypertension, especially body mass index (BMI) and smoking. A total of 192 control subjects (aged 45.87 +/- 3.0 years) and 206 patients with the essential hypertension (aged 48.71 +/- 8.42 years) were compared at three angiotensinogen gene polymorphisms by considering BMI and smoking status. No significant differences in genotype and/or allelic distribution for either A (-6) G ATG, M235T or T174M polymorphisms between the hypertensive and control groups were proved. Significantly more hypertensives than control persons with BMI above 25 kg/m(2) were observed (P(corr) = 0.009), independently on sex distribution. A percentage of 44.6% of smokers in the control group vs 46.0% of smokers in the hypertensive groups were found. No significant difference in concurrence of BMI above 25 kg/m(2) and positive smoking status between control and hypertensive subjects was found. Statistically significant differences were found between control and hypertensive subjects when compared distributions of subjects with certain genotypes of the three examined polymorphisms considering BMI (P(corr) = 0.0002 for AA+AG of A (-6) G ATG, P(corr) = 0.01 for CC + CT of T(174)M ATG and P(corr) = 0.01 for MT + TT of M235T ATG). No functional relationship among obesity and the examined polymorphisms in vivo are known. We conclude that a different distribution of BMI could influence the results of analyses of angiotensinogen gene polymorphisms in essential hypertension-control studies.

Topics: Alleles; Angiotensinogen; Body Mass Index; Case-Control Studies; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic

Molecular variants (M235T and T174M) in the angiotensinogen (AGT) gene and a mutation in the promoter region that involves the presence of an adenine (A) instead of a guanine (G) 6 bp upstream from the transcription initiation site (G-6A) have been reported to have a positive correlation with hypertension. This study evaluated the association of the M235T, T174M, and G-6A mutations of the AGT gene with hypertension in Taiwanese aboriginals.. This case-control study recruited 107 subjects with hypertension and 96 normotensive subjects from the Amis tribes of eastern Taiwan. Genomic DNA was amplified using the polymerase chain reaction (PCR) and the PCR product was analyzed using automated sequencing.. The frequencies of MM, MT, and TT genotypes at amino acid 235 were different between hypertensive (1%, 13%, 86%) and normotensive subjects (0%, 30%, 70%; p = 0.008), whereas the 174 variants of the AGT gene were not different between these two groups (1%, 14%, 85% in hypertensives, 1%, 17%, 82% in normotensives; p = 0.868). The distribution of GG, GA, and AA genotypes differed between the two groups (1%, 15%, 84% in hypertensives vs 1%, 31%, 68% in normotensives; p = 0.021). The frequency of the 235T allele was higher among hypertensives than normotensives (93 vs 85%; p = 0.015) and the odds ratio for association with the 235T allele (vs 235M) in hypertensives was 2.20. The frequency of the 174M allele was not different between the two groups (1 vs 1%). The frequency of the -6A allele was higher among hypertensives (83 vs 68%; p = 0.011) and the odds ratio association of hypertension with the -6A allele (vs -6G) was 2.18. Haplotype analysis showed that the -6A-235T allelic frequencies significantly differed between the two groups (chi 2 = 1.39, P = 0.001).. The prevalences of the 235T and -6A variants of the AGT gene in the Amis tribes of eastern Taiwan are high and are significantly associated with hypertension, whereas the 174M variant is not. The haplotype combining the 235T and -6A variants is also associated with hypertension. The prevalences of the 235T allele and -6A allele in this study and other studies in ethnic Chinese subjects are higher than those in Japanese.

Topics: Aged; Angiotensinogen; Female; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Native Hawaiian or Other Pacific Islander; Polymorphism, Genetic; Racial Groups; Taiwan

Hypertension-induced damage of kidney and heart is of major clinical relevance, but its pathophysiology is only partially understood. As there is considerable evidence for involvement of angiotensin II, we generated a new mouse model by breeding angiotensinogen (AOGEN) deficient mice with transgenic animals expressing the rat AOGEN gene only in brain and liver. This genetic manipulation overcame the hypotension of AOGEN-deficient mice and even caused hypertension indistinguishable in its extent from the parent transgenic mice with an intact endogenous AOGEN gene. In contrast to normal mice, however, crossbred animals lacked detectable expression of AOGEN in kidney and heart. As a consequence they showed markedly reduced cardiac hypertrophy and fibrosis. Furthermore, hypertension-induced alterations in kidney histology and function were less pronounced in crossbred mice than in equally hypertensive animals expressing AOGEN locally. The dysmorphogenesis observed in kidneys from AOGEN-deficient mice was absent in mice expressing this gene only in liver and brain. Our results support an important role of local AOGEN expression in hypertension-induced end-organ damage but not in the development of the kidney.

Topics: Angiotensinogen; Animals; Brain; Cardiomegaly; Disease Models, Animal; Fibrosis; Heart Diseases; Hypertension; Kidney Diseases; Liver; Mice; Mice, Transgenic; Myocardium; Organ Size; Organ Specificity; Renin-Angiotensin System

Isolated systolic hypertension (ISH) occurs predominantly in the elderly, with a considerable morbidity and mortality. Its etiology is unknown but is likely to involve a significant genetic component. The aim of this study was to examine the angiotensinogen gene in ISH. The M235T and G(- 6)A polymorphisms were genotyped by polymerase chain reaction (PCR) in 86 ISH patients and 120 normotensive controls. Plasma angiotensinogen concentration was determined in 198 subjects by an indirect radioimmunoassay technique. Angiotensinogen mRNA concentration was determined by quantitative competitive reverse transcription (RT)-PCR in subcutaneous adipose tissue from a subset of these patients (n = 8) and controls (n = 6). Both the M235T (p = 0.0015) and G(- 6)A (p = 0.029) polymorphisms were associated with ISH. Plasma angiotensinogen concentration was higher in patients than controls (p < 0.0001), but was not associated with genotype. Angiotensinogen mRNA concentration in adipose tissue from ISH subjects was significantly lower than in adipose tissue from normotensive subjects (p = 0.033). The association of angiotensinogen gene variants with ISH and the elevation of plasma angiotensinogen concentration in these patients suggests a role of the angiotensinogen gene in this form of hypertension. Angiotensinogen gene expression may be altered in ISH, but this requires further examination.

Topics: Aged; Angiotensinogen; Female; Genotype; Humans; Hypertension; Male; Polymorphism, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Human genetic studies and gene targeting techniques in mice suggest that the genes encoding renal apical Na transport proteins play an essential role in the control of extracellular fluid volume and blood pressure. Particularly, very significant advancements in understanding the role of these genes in Mendelian forms of hypertension or hypotension have been achieved in recent years. However, much progress still needs to be made in understanding the more common forms of human essential hypertension. In addition to the mouse models that should be very useful for investigating the mechanisms by which a mutation provokes the hypertensive phenotype, improved clinical phenotyping of patients is needed as well as the use of DNA chip techniques to unravel global gene interactions. Indeed, it is likely that most chronic blood pressure disturbances in a given environment result from a specific combination of polymorphisms or mutations rather than from unique genetic variants. Of equal importance will be definition of the various factors that regulate the expression and activity of the Na transport systems. These regulatory pathways and the responses to environmental factors such as dietary salt, stress, etc, may play a central role in determining the appearance, severity, and complications of essential hypertension.

Topics: Angiotensinogen; Animals; Biological Transport; Blood Pressure; Calmodulin-Binding Proteins; Carrier Proteins; Epithelial Sodium Channels; Humans; Hypertension; Kidney; Mice; Sodium; Sodium Channels; Sodium Chloride Symporters; Sodium-Hydrogen Exchangers; Sodium-Potassium-Chloride Symporters; Symporters

Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension and increased intrarenal AngII contents through multiple mechanisms, which may include sustained or increased local production of AngII. This study was designed to test the hypothesis that chronic AngII infusion increases renal angiotensinogen mRNA and protein levels, thus contributing to the increase in intrarenal AngII levels. AngII (80 ng/min) was infused subcutaneously for 13 d into Sprague-Dawley rats, using osmotic minipumps. Control rats underwent sham operations. By day 12, systolic arterial BP increased to 184 +/- 3 mmHg in AngII-treated rats, whereas values for sham-treated rats remained at control levels (125 +/- 1 mmHg). Plasma renin activity was markedly suppressed (0.2 +/- 0.1 versus 5.3 +/- 1.2 ng AngI/ml per h); however, renal AngII contents were significantly increased in AngII-treated rats (273 +/- 29 versus 99 +/- 18 fmol/g). Western blot analyses of plasma and liver protein using a polyclonal anti-angiotensinogen antibody demonstrated two specific immunoreactive bands, at 52 and 64 kD, whereas kidney tissue exhibited one band, at 52 kD. Densitometric analyses demonstrated that AngII infusion did not alter plasma (52- or 64-kD), renal (52-kD), or hepatic (52-kD) angiotensinogen protein levels; however, there was a significant increase in hepatic expression of the highly glycosylated 64-kD angiotensinogen protein, of almost fourfold (densitometric value/control value ratios of 3.79 +/- 1.16 versus 1.00 +/- 0.35). Renal and hepatic expression of angiotensinogen mRNA, which was examined by semiquantitative reverse transcription-PCR, was significantly increased in AngII-treated rats, compared with shamtreated rats (kidney, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 0.82 +/- 0.11 versus 0.58 +/- 0.04; liver, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 2.34 +/- 0.07 versus 1.32 +/- 0.15). These results indicate that increases in circulating AngII levels increase intrarenal angiotensinogen mRNA levels, which may contribute to the sustained renal AngII-generating capacity that paradoxically occurs in AngII-treated hypertensive rats.

Topics: Angiotensin II; Angiotensinogen; Animals; Base Sequence; Blotting, Western; DNA Primers; Gene Expression; Hypertension; Immunohistochemistry; Kidney; Liver; Male; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

Albuminuria predicts nephropathy-related mortality in Caucasian and Chinese populations. The involvement of renin-angiotensin system (RAS) gene polymorphisms in the pathogenesis of nephropathy has been described predominantly in Caucasian populations. We have previously suggested that the angiotensinogen 235T variant may be associated with nephropathy in diabetic Chinese.. To validate these findings and extend them to include non-diabetic nephropathy, we examined the association of albuminuria and gene polymorphisms of the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type I receptor A1166C polymorphisms in 614 Chinese subjects (66% type 2 diabetic, 16% normoglycemic hypertensives and 18% controls).. Obesity and higher blood pressure were associated with albuminuria in both diabetes and normoglycemic hypertension. In the diabetic group, albuminuria was also associated with increased insulin resistance and glycemic indices, duration of diabetes and adverse lipid profiles. Only the ACE gene polymorphism showed evidence of association with albuminuria, with the D allele being less frequent in the normoglycemic hypertensive patients with albuminuria (25.0%) than the controls (41.4%) or normoalbuminuric group (39.6%) and in those hypertensives at increased risk (albumin-to-creatinine ratio > 5.6 mg/mmol) of end-stage renal disease than those at lower risk (all p < 0.05), but not in the diabetic group. The D allele was also less prevalent in the total (31.9%) and normoalbuminuric (32.2%) diabetic groups than in the controls (p < 0.05).. In this cohort of Chinese subjects, the ACE gene polymorphism D allele was less frequent in normoglycemic hypertensive patients with albuminuria and in type 2 diabetes.

Topics: Adult; Albuminuria; Angiotensinogen; Blood Glucose; China; Diabetes Mellitus, Type 2; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System

Plasma renin activity (PRA), active renin (AR), prorenin, and angiotensinogen were assessed in 486 hypertensive and 175 normotensive subjects with a sodium intake of 10 or 200 mEq/d during supine and upright posture and after infusion of angiotensin II. PRA and AR levels were compared in hypertensive subjects in each condition. With low sodium intake, particularly while upright, there was a significant correlation between PRA and AR. In upright subjects with low sodium intake who had a PRA of 2.4 ng/mL per hour or less (1.85 nmol.L-1.h-1 or less), the correlation was also strong. With high sodium intake, the correlation was weaker. With intermediate sodium excretion, the correlation was intermediate. Prorenin was less predictive of PRA than was AR, and angiotensinogen had a marginal role. Using PRA during sodium restriction while upright as the standard for determining renin status, the precision of AR for predicting renin status was excellent. AR may be used for surrogate assessment of the renin-angiotensin system activity when the system is activated.

Topics: Angiotensin II; Angiotensinogen; Enzyme Precursors; Humans; Hypertension; Immunoradiometric Assay; Renin; Renin-Angiotensin System; Reproducibility of Results; Sodium Chloride, Dietary; Supine Position

In Chinese populations, hypertension is common and is a major risk factor for cerebrovascular and coronary heart disease, particularly when associated with diabetes. The clustering of these disorders and dyslipidemia and obesity is termed the metabolic syndrome and is increasing in prevalence in the populations of modernizing Asian nations. The renin-angiotensin system (RAS) helps maintain blood pressure and salt homeostasis and may play a role in the pathogenesis of aspects of the metabolic syndrome. We investigated three RAS gene polymorphisms--the ACE insertion/deletion (I/D), angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms--for a possible role in modulating these disorders in 853 Chinese subjects with varying components of the metabolic syndrome.. The three gene polymorphisms of this cross-sectional study were detected using polymerase chain reaction-based protocols. The genotype frequencies were compared between the controls (n = 119) and both overlapping and nonoverlapping groups of patients with type 2 diabetes, hypertension, and dyslipidemia using chi2 test. Differences in levels of the biochemical parameters between the genotypes were determined using analysis of variance.. No significant relationship was identified between these polymorphisms and blood pressure in this population. Although the AT1RA1166C polymorphism was not associated with any aspect of the metabolic syndrome examined, there was limited evidence to suggest that the AGT M235T polymorphism may be associated with cholesterol levels. The ACE I allele was significantly more frequent in each group comprising subjects with type 2 diabetes/glucose intolerance (GIT), and the I allele was associated with higher fasting plasma glucose levels.. These findings suggest that these polymorphisms are unlikely to be involved in the pathogenesis of hypertension. The ACE I/D polymorphism was associated with the metabolic syndrome, having a higher frequency of I allele-containing genotypes in those groups, but this appeared to result predominantly from the relationship with type 2 diabetes/GIT in this population of Chinese subjects.

Topics: Adult; Alleles; Angiotensinogen; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Deletion; Genotype; Glucose Intolerance; Hong Kong; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

A common variant at codon 235 of the angiotensinogen gene with methionine to threonine amino acid substitution (AGT M235T) has been reported as a genetic risk for essential hypertension. However, the frequency of AGT T235 was heterogeneous among races, and a positive association between AGT M235T and hypertension was not settled. To examine the association in a general population of Japanese (n=4013), we introduced the TaqMan polymerase chain reaction method and examined the relation between hypertension and T+31C polymorphism, which was in absolute linkage disequilibrium with AGT M235T. The C+31 allele of AGT was significantly associated with the positive family history of hypertension (FH) but not with the presence of hypertension or blood pressure. The subjects with CC tended to have hypertensive relatives, especially a hypertensive father or siblings, and its statistical significance was stronger in men. Adjustment of confounding factor did not alter the results of simple association study, suggesting that this positive association with FH is independent and significant. Our findings revealed that the TaqMan polymerase chain reaction method is a powerful tool for genetic association study with a large number of subjects and that AGT T+31C is significantly associated with paternal FH.

Topics: Aged; Alleles; Analysis of Variance; Angiotensinogen; Blood Pressure; Cohort Studies; DNA; Family Health; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide

The systemic renin-angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of 2-kidney, 1 clip (2K1C) hypertension. Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, but the hypertension is sustained for months. We hypothesized that in this phase the brain RAS contributes to the maintenance of high BP. To test the hypothesis, we studied the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and the angiotensin II (Ang II) type 1a receptor (AT(1)R) with intracerebroventricular injections of antisense oligonucleotides (AS-ODNs). The response of systolic BP (SBP) to AS-ODNs to AGT mRNA was studied in 2K1C rats at 6 months after clipping, and the response to AS-ODNs to AT(1)R mRNA was studied at 10 months after clipping. Intracerebroventricular injection of AS-ODN-AGT (200 microgram/kg, n=5) significantly decreased SBP (-22+/-6 mm Hg, P<0.05) compared with the sense ODN (n=5) and saline (n=3) groups. Intracerebroventricular injection of AS-ODN-AGT reduced the elevated hypothalamic Ang II level. The hypothalamic Ang II content in sense ODN and saline groups was significantly (P<0.05) higher than in the nonclipped group. Compared with inverted ODN, intracerebroventricular injection of AS-ODN-AT(1)R (250 microgram/kg, n=6) significantly decreased SBP (-26+/-8 mm Hg, P<0.05) for 3 days after injection. This was a brain effect because intravenous AS-ODN-AT(1)R at a dose of 250 to 500 microgram/kg did not affect SBP. These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic 2K1C hypertension.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Blood Pressure; Brain; Chronic Disease; Hypertension; Hypertension, Renovascular; Hypothalamus; Injections, Intraventricular; Male; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Time Factors

Angiotensinogen (AGT), one of the major components in the renin-angiotensin system, has been linked to hypertension in humans and animals. We have previously systemically administered antisense oligonucleotides and plasmid vectors with DNA that targeted AGT and attenuated hypertension in spontaneously hypertensive rats. The aim of the present study was to prolong the effect of antisense treatment by the use of a recombinant adeno-associated viral (rAAV) vector targeted to AGT. Using a model of lifelong hypertension in which 5-day-old spontaneously hypertensive rats are treated, a single intracardiac injection of rAAV-AGT-antisense (rAAV-AGT-AS) delayed the onset of hypertension for 91 days and significantly attenuated hypertension in adulthood for up to 6 months. Systolic blood pressure was always lower, by up to 23 mm Hg in the AS-treated group. The vector was stable and expressed a reporter gene in liver, kidney, and heart. The rAAV-AGT-AS treatment significantly decreased left ventricular hypertrophy (P=0.01) and also lowered levels of AGT in the liver (2.78+/-0.61 microgram/g tissue versus 5.23+/-0.41 microgram/g tissue for the sense-treated group, P<0.01). Measurement of liver transaminases showed no evidence for liver toxicity. We conclude that rAAV-AGT-AS offers a safe, stable approach for gene therapy of hypertension.

Topics: Adenoviridae; Age Factors; Angiotensinogen; Animals; Blood Pressure; Genes, Reporter; Genetic Therapy; Genetic Vectors; Hypertension; Hypertrophy, Left Ventricular; Kidney; Liver; Myocardium; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Time Factors; Transaminases

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. Urinary nitrate plus nitrite (NO(x)) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F(2alpha) levels, renal XOR activity, and, to a degree, NO(x) excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II-induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.

Topics: Acetylcholine; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Dinoprost; Disease Models, Animal; Endothelium, Vascular; F2-Isoprostanes; Humans; Hypertension; Ketone Oxidoreductases; Male; Nitrates; Nitrites; Nitroprusside; Norepinephrine; Rats; Rats, Sprague-Dawley; Renal Artery; Renin; Superoxide Dismutase; Tetrazoles; Valine; Valsartan; Vasoconstrictor Agents; Vasodilation

To study whether the brain renin-angiotensin system plays a role in the long-term and short-term control of blood pressure and heart rate variability, we examined in transgenic rats [TGR(ASrAOGEN)] with low brain angiotensinogen levels the 24-hour variation of blood pressure and heart rate. Telemetry recordings were made during basal and hypertensive conditions induced by a low-dose subcutaneous infusion of angiotensin II for 7 days. Short-term blood pressure and heart rate variability were evaluated by spectral analysis, and as a measure of baroreflex sensitivity, the average transfer gain between the pressure and heart rate variations was calculated. During the angiotensin II infusion in control but not TGR(ASrAOGEN) rats, the 24-hour rhythm of blood pressure was inverted (5.8+/-2 versus -0.4+/-1.8 mm Hg/group of day-night differences of blood pressure, P<0.05, respectively). In both the control and TGR(ASrAOGEN) rats, the 24-hour heart rate rhythms remained unaltered and paralleled those of locomotor activity. The transfer gain between 0.3 to 0.6 Hz was significantly higher in TGR(ASrAOGEN) than in control rats during control (0.71+/-0.1 versus 0.35+/-0.06, P<0.05) but not during angiotensin II infusion (0.6+/-0.07 versus 0.4+/-0.1, P>0.05). These results demonstrate that the brain renin-angiotensin system plays an important role in mediating the effects of angiotensin II on the circadian variation of blood pressure. Furthermore, these data indicate that a permanent deficiency in the brain renin-angiotensin system alters the reflex control of heart rate in rats.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Baroreflex; Blood Pressure; Brain; Circadian Rhythm; Heart Rate; Hypertension; Locomotion; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Telemetry; Time Factors

In the present study, we tested the hypothesis that the Met235Thr and Thr174Met mutations were associated or not with elevated blood pressure. We genotyped 9100 women and men from the Danish general population, of whom 54% had elevated blood pressure. Of the 9100, 41% and 12% carried the Thr235 and Met174 mutations, respectively; the Met174 mutation always occurred on the same allele as the Thr235 mutation. On multifactorial logistic regression analysis, women homozygous for Thr235 versus noncarriers had an odds ratio for elevated blood pressure of 1.29 (95% CI 1.05 to 1.58), which increased to 1.50 (1.15 to 1.96) if they also were homozygous for Thr174 (noncarrier of Met174). Women homozygous for Thr235 also had an increased risk of isolated elevated systolic blood pressure (1.37; 1.02 to 1.84) and of mild blood pressure elevation (1.40; 1.10 to 1.77). We found no statistically significant association between elevated blood pressure and genotype in men or among genotype and systolic blood pressure, diastolic blood pressure, or pulse pressure in either gender. Homozygosity for both Thr235 and Thr174 was associated with a 10% increase in plasma angiotensinogen levels in both genders compared with homozygosity for Met235 and Thr174; however, systolic and diastolic blood pressures were positively correlated to plasma angiotensinogen levels in women only. In conclusion, in this large-scale study of the general population, double homozygosity for Thr235 and Thr174 in the angiotensinogen gene is associated with a 10% increase in angiotensinogen levels and is a risk factor for elevated blood pressure in women but not in men.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Angiotensinogen; Blood Pressure; Body Mass Index; Female; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Mutation; Odds Ratio; Risk Factors; Sex Factors

1. Fetal exposure to an adverse intrauterine environment has been linked with cardiovascular and metabolic disease later in life. We have shown previously, in sheep, that brief exposure (48 h) to maternally administered dexamethasone (0.28 mg/kg per day) at 27 days of gestation (prenatal treatment group (PTG) 1; term approximately 150 days), but not at 64 days of gestation (PTG2), produced hypertensive offspring at 40 months of age. The present study aimed to determine whether the elevated blood pressure in these sheep was associated with an altered peripheral renin-angiotensin system (RAS). 2. Measurements of the basal levels of the RAS components (renin, angiotensinogen, angiotensin (Ang) I, angiotensin- converting enzyme (ACE), AngII and Ang-(1-7)) were made. In addition, we studied the effect of a peripherally administered AngII type 1 (AT1) receptor antagonist (irbesartan at 1.02 mg/kg per h) on mean arterial pressure (MAP) over 4.5 h. 3. There was no significant difference in basal plasma concentrations of the components of the RAS measured between control (n = 7) and PTG1 (n = 5) or PTG2 (n = 6) animals. The MAP in PTG1 was significantly higher than in the control group during both vehicle infusion and AT1 receptor blockade. The effect of 4.5 h irbesartan (1.02 mg/kg per h) infusion on blood pressure was similar between the groups. 4. In conclusion, intrauterine exposure for 48 h to maternally administered dexamethasone at 27 days of gestation caused elevated blood pressure in adult sheep that does not appear to be associated with an alteration in the peripheral RAS.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Dexamethasone; Female; Glucocorticoids; Hypertension; Irbesartan; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Sheep; Tetrazoles; Vasoconstrictor Agents

Arterial stiffness is associated with excess morbidity and mortality, independently of other cardiovascular risk factors. Age is the main determinant responsible for arterial wall changes leading to arterial stiffening. Environmental and genetic factors may however influence the magnitude of the effects of age on large artery stiffness.. The present study assessed whether or not the relationship between age and aortic stiffness was influenced by genetic variants of angiotensinogen (AGT 174T/M, 235M/T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 1166A/C, -153A/G) and aldosterone synthase (CYP11B2 -344T/C). This study was realized in 441 untreated hypertensive subjects of European origin (aged 18-74 years). Aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWV).. Carriers of the angiotensin II type 1 receptor -153G allele showed a steeper age/PWV relationship than the AT1 -153AA subjects. The effect of the AT1 -153A/G polymorphism on aortic stiffness became apparent after the age of 55 years. In subjects with the AT1 1166C allele, the relationship age/PWV is shifted upward, indicating higher values of aortic stiffness at any age compared to the AT1 1166AA patients. Carriers of both the AT1 1166C and -153G alleles presented the additive effects of these 2 genotypes on aortic stiffness. Angiotensinogen, ACE and CYP11B2 genotypes did not influence the effects of age on PWV.. AT1 receptor genotypes could influence arterial ageing in hypertensive subjects. These results also show that the association between genotypes and arterial stiffness may manifest itself later in life.

Topics: Adolescent; Adult; Age Factors; Aged; Angiotensinogen; Aorta; Base Sequence; Biomechanical Phenomena; Cytochrome P-450 CYP11B2; DNA Primers; Female; Genotype; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Risk Factors; Vascular Resistance

Tissue renin-angiotensin systems are known to behave differently from the circulating renin-angiotensin system (RAS). It has already been proposed that not only the circulating RAS, but also RAS localized in the cardiac tissue plays an important role in the heart failure. The objective of this study was to compare the gene expression of individual components of the renin-angiotensin system in hearts of normotensive and hypertensive rats. Two genetically hypertensive rat strains--spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic rats (HTG)--were compared with Wistar-Kyoto (WKY) and Lewis (LEW) normotensive controls. In addition, developmental changes in gene expression of individual components of cardiac RAS were studied in 20-day-old fetuses, 2-day-old newborns and 3-month-old HTG and LEW rats. In our study, the angiotensinogen gene expression did not differ either among adult normotensive and hypertensive strains, or during development. In contrast, the renin gene expression was significantly increased in hearts of hypertensive compared to normotensive rats. Moreover, a 5-fold increase of renin mRNA was observed in hearts of HTG rats between day 2 and the third month of age. There was also an age-dependent increase of ACE gene expression in both HTG and LEW rats which was substantially delayed in HTG hearts. In conclusion, the results of our study suggest that overexpression of the cardiac renin gene in hypertensive strains could participate in the structural and functional changes of the heart during the development of hypertension.

Topics: Angiotensinogen; Animals; Gene Expression; Hypertension; Hypertriglyceridemia; Male; Myocardium; Polymerase Chain Reaction; Rats; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To investigate the relationship between the A-6G variant in the promoter of the angiotensinogen gene and essential hypertension in Han, Tibetan, and Yi populations. All patients with essential hypertension were selected by WHO criteria. And the polymorphism of the A-6G variant was determined by PCR/RFLP. The data were analyzed by t test and chi2 test. There was no significant difference in the genotype or allele frequencies between normotensives and hypertensives in the Han, Tibetan, and Yi populations, respectively. However, when the subjects were divided into male and female subgroups, the genotype distributions among hypertensives and normotensives of the Tibetan female group were as follows: AA, 37% vs. 48%; AG, 52% vs. 48%; GG, 11% vs. 4%, respectively and the frequency of the G allele was significantly higher in hypertensives than in normotensives in the Tibetan female group (0.37 vs. 0.28, chi2=4.25, p<0.05). In addition, we observed that there was a significant difference between the Han and Tibetan normotensive groups in the distributions of the allele and genotype frequencies of the A-6G variant. The frequency of the G allele was 0.29 and 0.17 in the Tibetan normotensive and Han groups, respectively (p<0.001). The G allele of the A-6G variant was associated with hypertension in the Tibetan females, but not in the Yi or Han females. And we confirmed that there was a significant difference in the prevalence of the allele frequencies of the A-6G variant between the Han and Tibetan normotensive groups.

Topics: Adult; Angiotensinogen; China; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Prevalence; Risk Factors; Tibet

Oral contraceptives (OC) usage increases serum angiotensinogen levels to three to five times normal and about 5% of these women develop arterial hypertension. The genetic contribution to this susceptibility to OC-induced hypertension is poorly understood. We have analyzed the genotypes of 149 hypertensive and 101 normotensive women using oral contraceptives, for three genetic polymorphisms in genes of the renin-angiotensin system: an insertion/deletion (I/ D) in the angiotensin converting enzyme (ACE) gene, the T235M polymorphism of the angiotensinogen gene (AGT) and a point mutation in its promoter.. After cessation of oral contraception the mean arterial pressures of the hypertensive women were separable into two non-overlapping groups; 88 of the women remained hypertensive and 61 returned to normal blood pressure. Both groups of hypertensive women had a similarly higher frequency of hypertensive relatives than the normotensive women, but were otherwise similar. The 235T allele of AGT was significantly increased in frequency in the 61 oral contraceptive-inducible hypertensive women compared with the controls and the 88 women that remained hypertensive. The ACE I/D genotypes were similarly distributed within the three groups of women, but were distinctly non-random in the oral contraceptive-induced hypertensive women when they were also classified by AGT genotype.. This statistical interaction of genotype frequencies suggests that the genetic basis of susceptibility to OC-induced hypertension is complex.

Topics: Adult; Alleles; Angiotensinogen; Contraceptives, Oral; DNA Transposable Elements; Female; Gene Deletion; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Peptidyl-Dipeptidase A; Point Mutation; Polymorphism, Genetic; Reference Values

The complexity of factors influencing the development of hypertension (HTN) in African Americans has given rise to theories suggesting that genetic changes occurred due to selection pressures/genetic bottleneck effects (ie, constriction of existing genetic variability) over the course of the slave trade. Ninety-nine US-born and 86 African-born health professionals were compared in a cross-sectional survey examining genetic and psychosocial predictors of HTN. We examined the distributions of three genetic loci (G-protein, AGT-235, and ACE I/D) that have been associated with increased HTN risk. There were no significant differences between US-born African Americans and African-born immigrants in the studied genetic loci or biological variables (eg, plasma renin and angiotensin converting enzyme activity), except that the AGT-235 homozygous T genotype was somewhat more frequent among African-born participants than US-born African Americans. Only age, body mass index, and birthplace consistently demonstrated associations with HTN status. Thus, there was no evidence of a genetic bottleneck in the loci studied, ie, that US-born African Americans have different genotype distributions that increase their risk for HTN. In fact, some of the genotypic distributions evidenced lower frequencies of HTN-related alleles among US-born African Americans, providing evidence of European admixture. The consistent finding that birthplace (ie, US vs Africa) was associated with HTN, even though it was not always significant, suggests potential and unmeasured cultural, lifestyle, and environmental differences between African immigrants and US-born African Americans that are protective against HTN.

Topics: Adult; Africa; Analysis of Variance; Angiotensinogen; Anthropometry; Black or African American; Black People; Blood Glucose; Body Mass Index; Chi-Square Distribution; Cross-Over Studies; Emigration and Immigration; Female; Genetic Predisposition to Disease; Genetic Testing; GTP-Binding Proteins; Health Surveys; Humans; Hypertension; Life Style; Logistic Models; Male; Middle Aged; Pedigree; Peptidyl-Dipeptidase A; Prejudice; Risk Assessment; Risk Factors; Sampling Studies; United States

Many recent case-control studies have suggested a significant relationship between M235T (the substitution of threonine for methionine at position 235 codon) polymorphism of the angiotensinogen (AGT) gene and hypertension. To investigate whether the M235T polymorphism of AGT gene affects the incidence of hypertension, a retrospective cohort study was performed among Japanese workers. The subjects were Japanese workers at an occupational site in Shimane Prefecture in Japan. The baseline data were set at the received regular health examination in 1992, and a retrospective cohort study was performed for analyzing the incidence of hypertension in 1998. The rates of M235M (MM), M235T (MT) and T235T (TT) genotypes were 4%, 32% and 64%, respectively. The relative risks of MT and TT against MM for the incidence of hypertension by single variance analysis were 1.47 [95% confidence interval (CI) 0.50 - 4.33] and 1.35 (95% CI 0.47 - 3.90), respectively. The relative risks of MT and TT against MM for the incidence of hypertension, adjusted for sex, age, body mass index, fasting glucose and cigarette smoking, drinking and exercise in 1992, were 1.49 (95% CI 0.49 - 4.53) and 1.25 (95% CI 0.42 3.74), respectively. The data from this study suggest that the M235T polymorphism of AGT gene has a weak role in the manifestation of hypertension. Further comprehensive studies are needed to resolve this issue.

Topics: Adult; Angiotensinogen; Blood Glucose; Body Mass Index; Chi-Square Distribution; Female; Genotype; Humans; Hypertension; Incidence; Japan; Logistic Models; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Retrospective Studies; Risk Factors

To investigate whether angiotensinogen(AGT) M235T, angiotensin II type I receptor(AT(1)R) gene A1166C and angiotensin converting enzyme(ACE) gene I/D polymorphism are implicated in human essential hypertension(HT) in Chinese.. Polymerase chain reaction(PCR) and PCR combined with restriction enzyme digestion were used to detect AGT gene M235T, AT(1)R gene A1166C variations and ACE gene I/D polymorphism in 161 hypertensive patients and 134 normotensive controls.. No statistically significant differences were found in frequencies of the ACE D allele, AGT gene 235T and AT(1)R A1166C between hypertensive patients and normotensive controls, but in hypertensive patients aged <60 years the frequencies of the ACE D allele and AGT gene 235T were significantly higher than those of the normotensive controls (P<0.05). The analysis of combined genotypes of AGT gene and ACE gene showed that the combined genotypes of DD-TT and ID-TT were significantly higher in hypertensive patients than in normotensive controls. Significant relationships between the ACE genotype and serum ACE activity were found in both groups(P<0.05).. The ACE D allele and AGT 235T polymorphism may be involved in the early occurrence of HT. The combined genotypes of DD-TT and ID-TT may be a dangerous genetic factor for HT in Chinese.

Topics: Adult; Aged; Angiotensinogen; Angiotensins; Asian People; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin

In addition to the normally prevalent low molecular weight angiotensinogen (LMrA), significant quantities of a high molecular weight angiotensinogen (HMrA) are present in the human pregnant state. Previous studies have documented that 47% of women who develop pregnancy-induced hypertension (PIH) have a significantly elevated plasma HMrA/LMrA ratio. The purpose of this study is to establish whether or not the increase in the HMrA/LMrA ratio precedes the development of hypertension. Serial plasma samples were collected from a group of women throughout their pregnancy. High molecular weight angiotensinogen and LMrA levels in the samples from these women were determined. Fifteen of these women developed PIH. Seven women in the PIH group had a significantly elevated plasma HMrA/LMrA ratio. There was no consistent relationship between the elevation of the HMrA/LMrA ratio and the onset of hypertension. Three women had an elevated HMrA/LMrA ratio before the development of hypertension. In one woman the two events occurred simultaneously, and in three women the HMrA/LMrA ratio was elevated only after the development of hypertension. The current study shows that the development of hypertension during pregnancy is not the primary biologic signal for elevation of the plasma HMrA/LMrA ratio. Other parameters associated with fetal distress or abnormal development of placental circulatory systems must be involved in increasing the HMrA/LMrA ratio. It is proposed that the elevation of the HMrA/LMrA ratio is a mechanism by which the placental tissue specific renin-angiotensin system is attenuated.

Topics: Angiotensinogen; Female; Humans; Hypertension; Molecular Weight; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Cardiovascular

In addition to the circulatory renin (REN)-angiotensin system (RAS), a tissue RAS having an important role in cardiovascular function also exists in the central nervous system. In the brain, angiotensinogen (AGT) is expressed in astrocytes and in some neurons important to cardiovascular control, but its functional role remains undefined. We generated a transgenic mouse encoding the human AGT (hAGT) gene under the control of the human glial fibrillary acidic protein (GFAP) promoter to experimentally dissect the role of brain versus systemically derived AGT. This promoter targets expression of transgene products to astrocytes, the most abundant cell type expressing AGT in brain. All transgenic lines exhibited hAGT mRNA expression in brain, with variable expression in other tissues. In one line examined in detail, transgene expression was high in brain and low in tissues outside the central nervous system, and the level of plasma hAGT was not elevated over baseline. In the brain, hAGT protein was mainly localized in astrocytes, but was present in neurons in the subfornical organ. Intracerebroventricular (ICV) injection of human REN (hREN) in conscious unrestrained mice elicited a pressor response, which was abolished by ICV preinjection of losartan. Double-transgenic mice expressing the hREN gene and the GFAP-hAGT transgene exhibited a 15-mm Hg increase in blood pressure and an increased preference for salt. Blood pressure in the hREN/GFAP-hAGT mice was lowered after ICV, but not intravenous losartan. These studies suggest that AGT synthesis in the brain has an important role in the regulation of blood pressure and electrolyte balance.

Topics: Angiotensinogen; Animals; Astrocytes; Blood Pressure; Brain; Dose-Response Relationship, Drug; Drinking; Gene Expression; Glial Fibrillary Acidic Protein; Humans; Hypertension; Injections, Intravenous; Injections, Intraventricular; Losartan; Mice; Mice, Transgenic; Neurons; Organ Specificity; Promoter Regions, Genetic; Renin; RNA, Messenger; Subfornical Organ; Transgenes; Water-Electrolyte Balance

We investigated cardiac function in rats transgenic for the human renin and angiotensinogen genes (TGR) to test the hypothesis that elevated local angiotensin II precipitates adrenergic dysfunction and abnormal contractile function.. Hearts from TGR and Sprague-Dawley control rats, aged 6 weeks, were studied using the Langendorff model and papillary muscle preparations (n = 6-10 per group). Incremental isoproterenol (1 - 1000 nmol/l) and external Ca2+-concentrations (0.75-6.0 mmol/l) were tested. Cardiac protein and mRNA expression levels were determined by Western blot and RNAase protection assay.. TGR rats showed left ventricular hypertrophy (54%), higher blood pressures (76 mmHg), and elevated plasma renin activity (seven-fold) compared to controls (P < 0.01). The effect of isoproterenol on TGR rat systolic and diastolic left ventricular performance was decreased in both in-vitro models compared to controls (two- to threefold, P < 0.01). TGR rat papillary muscles showed impaired force generation with abnormal basal and Ca2+-dependent relaxation. Gialpha2 and Gialpha3 protein levels were increased (20-30%) and SERCA2a and adenylyl cyclase protein levels were decreased (23 and 37%, respectively) in TGR hearts compared to controls, while Gsalpha or beta1 and beta2-receptor levels were unchanged. Cardiac angiotensin converting enzyme and atrial natriuretic peptide mRNA levels were increased more than four-fold in TGR with no differences for the angiotensin type1 receptor, beta1-receptor, SERCA2a, phospholamban, adenylyl cyclase V and angiotensinogen genes.. TGR rat hearts develop severe adrenergic dysfunction with decreased adenylyl cyclase and abnormal intracellular Ca2+-homeostasis. Our findings emphasize angiotensin II as a major risk factor promoting early functional decline in cardiac hypertrophy. The data may have implications for patients with activating polymorphisms of the renin-angiotensin system and support the need for an early therapeutic intervention.

Topics: Adrenergic beta-Agonists; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Calcium; Coronary Circulation; Humans; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Reference Values; Renin; Ventricular Function, Left

Topics: Angiotensinogen; Cardiovascular Diseases; Endocrinology; Endothelins; Ghrelin; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Peptide Hormones; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors

We have studied the role of three polymorphic genes of the renin-angiotensin system (RAS) as independent risk factors for myocardial infarction (MI) and their correlation with three of the major coronary risk factors: serum cholesterol (CH), hypertension (HT) and smoking (SM). A population of 392 men was genotyped for the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion of the angiotensin-converting enzyme (ACE) and the all66c of the angiotensin-II type 1 receptor (AT1R), by means of polymerase chain reaction (PCR) and restriction enzyme analysis. It was observed that the T allele frequency increased significantly in the MI with HT, CH, and SM subgroup (0.58 vs 0.31) (p<0.01). In contrast, the M allele frequency was higher in the MI without HT, CH, and SM (0.69 vs 0.42) (p<0.01). A strong association between the MM genotype and MI (p<0.001, odds ratio=4.29, confidence interval=1.95-9.42) was found when age-matched MM control subjects were compared to MI individuals with none of the other known major coronary risk factors. Futhermore, subjects with the MM genotype showed a significantly higher plasma renin activity (PRA) profile than those with the TT genotype (p<0.001). It can be concluded that the M allele is an independent risk factor for MI and the T allele modified the risk when other major risk factors are present.

Topics: Adult; Alleles; Amino Acid Substitution; Angiotensinogen; Cholesterol; DNA; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Risk Factors; Smoking

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na(+) intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (P=0.0001). Blacks, on the other hand, showed no gender difference (P=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.

Topics: Adrenal Glands; Adult; Age Factors; Aldosterone; Angiotensin II; Angiotensinogen; Black People; Female; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Potassium; Potassium, Dietary; Renin; Sex Factors; White People

Blood pressure is a quantitative multifactorial trait influenced by environmental and genetic determinants. Although several candidate genes have been associated with the development of essential hypertension, the mechanisms of individual susceptibility still remain unclear. Knowledge on the distribution of genetic polymorphisms in different populations is fundamental for the assessment of the predictive value of genetic variation.. We genotyped 300 healthy normotensive subjects from the Italian population for three polymorphisms, at the angiotensinogen (AGT, M and T), angiotensin II type 1 receptor (ATIR, A and C) and angiotensin-converting enzyme (ACE, D and I) genes. Polymorphisms were analyzed by polymerase chain reaction and restriction enzyme digestion. Statistical analysis was performed to verify the agreement with the Hardy-Weinberg equilibrium.. The observed allelic distribution was in accordance with estimates reported for Caucasian populations. Variant allelic frequencies were 0.36 for the T and C alleles at the AGT andAT1R locus and 0.47 for the I allele of the ACE gene. AT1R and ACE genotype frequencies were in Hardy-Weinberg equilibrium, while there was a deviation of the AGT genotypes from those predicted by the equation.. The studied polymorphisms are largely distributed in the Italian population sample, with a frequency of homozygous subjects for mutant alleles ranging from 9 to 22%. Epidemiology of mutations in the genes involved in blood pressure regulation provides tools to evaluate susceptibility to hypertension.

Topics: Adult; Alleles; Angiotensinogen; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Italy; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Seroepidemiologic Studies

The aim of the present study was to determine if there is an association of different gene polymorphisms of renin-angiotensin system and left ventricular hypertrophy (LVH) in patients with essential hypertension (EH) in St Petersburg population.. We examined 156 patients (the mean age 49+/-8 years) with mild-to-moderate EH recruited from the general population of the outpatient clinic. Left ventricular mass was measured by echocardiography and left ventricular mass index (LVMI) was calculated. Subjects were genotyped for I/D polymorphism of the angiotensin-converting enzyme (ACE) gene, A1166C polymorphism of the AT1 receptor gene, M235T polymorphism of angiotensinogen gene and -6G/A polymorphism of its promoter region.. Genotype distribution of the sample obeyed Hardy-Weinberg equilibrium and was comparable to that reported previously for hypertensive individuals. Groups of patients with II, ID and DD polymorphism of ACE gene did not differ significantly in their LVMI levels. Furthermore, neither ID ACE-gene polymorphism nor ATI-receptor gene and angiotensinogen gene polymorphism was associated with LVH. Additionally, no any significant gene-gene interactions were found to be associated with LVH in the group studied.. In the light of these observations it seems reasonable to make a preliminary conclusion about lack of association between LVH and distinct polymorphisms of renin-angiotensin system genes in the population studied.

Topics: Adult; Angiotensinogen; Chi-Square Distribution; Electrocardiography; Female; Genetic Testing; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Russia

The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is advanced as a novel and suitable non-primate model of pregnancy-associated hypertension and fetal growth restriction because it simultaneously has spontaneous pregnancy-associated hypertension, small for gestational age (SGA) offsprings, and altered placental gene expression. Pregnancy-associated hypertension is a major contributor to maternal and fetal morbidity and mortality with the potential to result in maternal death and the need for iatrogenic preterm delivery. It has been reported to develop spontaneously in humans, but not in animals; consequently, progress in identifying the cause and pathogenesis of this disorder has been hampered. Spontaneous hypertension and heart failure rats develop hypertension spontaneously as they age, therefore we sought to determine whether these rats developed hypertension and SGA offsprings during pregnancy. Our results show that systolic blood pressure (BP) increased >40 mm Hg by the end of the first trimester and remained at this elevated level for the remainder of pregnancy, but decreased after parturition. Placenta weights of SHHF rats (0.60 +/- 0.02 g, n = 36) were significantly higher than Wistar-Kyoto (WKY) rats (0.42 +/- 0.01 g, n = 22, P < .05), but pup weights were significantly lower (2.68 +/- 0.06 g for SHHF rats compared to 3.24 +/- 0.06 g for WKY controls, P < .05). Histologic examination revealed pathologic lesions in neither heart, liver, placenta, nor kidney. L-Arginine administered in drinking water prevented the elevation of BP, particularly during the third trimester. Placentas from SHHF rats displayed altered expression of several genes whose protein products have been implicated in preeclampsia, including serotonin receptor, sodium channel, carbonic anhydrase, estrogen receptor regulator, major histocompatibility complex proteins, superoxide dismutase, and angiotensiogen. In addition, gene expression profiling showed alteration of a number of subcellular putative myristoylproteins not previously associated with preeclampsia, particularly those engaged in post-translational modifications in the placenta. Thus, SHHF rats may be a valuable tool, because it simultaneously has spontaneous pregnancy-associated hypertension, SGA offsprings, and altered placental gene expression.

Topics: Angiotensinogen; Animals; Birth Weight; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Weight; Gene Expression Profiling; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Protein Processing, Post-Translational; Rats; Rats, Inbred WKY; Rats, Mutant Strains

We analyzed the association between salt sensitivity in essential hypertension and 8 genetic polymorphisms in 6 genes of the renin-angiotensin aldosterone system. Seventy-one patients with essential hypertension were classified as salt sensitive or salt resistant by means of the 24-hour ambulatory blood pressure (BP) change to high salt intake. The polymorphisms evaluated correspond to the following genes: ACE (I/D), angiotensinogen (M235T), angiotensin II type 1 receptor (A1166C), 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) (G534A), aldosterone synthase (C-344T and Intron 2 conversion), and the mineralocorticoid receptor (G3514C and A4582C); all were determined using standard polymerase chain reaction methods. Thirty-five patients (49%) were classified as salt sensitive. We analyzed the BP response to high salt intake among genotypes and found a significant association for ACE I/D and 11betaHSD2 G534A polymorphisms. Patients homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake than did patients homozygous for the deletion allele (DD). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension was also significantly higher (P=0.003) in II (68%) and DI patients (59%) compared with DD hypertensives (19%). With respect to 11betaHSD2 G534A, patients with the GG genotype had a significantly higher systolic BP increase with high salt intake than did GA patients. In addition, plasma renin activity suppression in response to high salt was significantly greater in GA patients than in GG patients. The prevalence of salt-sensitive hypertension was 14.3% in GA patients and 50.8% in GG patients (P=0.067). In conclusion, the I allele of ACE I/D polymorphism is significantly associated to salt-sensitive hypertension. The BP response to high salt intake was different among genotypes of ACE I/D and 11betaHSD G534A, suggesting that these polymorphisms may be potentially useful genetic markers of salt sensitivity.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Angiotensinogen; Blood Pressure; Cytochrome P-450 CYP11B2; Female; Humans; Hydroxysteroid Dehydrogenases; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Mineralocorticoid; Renin-Angiotensin System; Sodium, Dietary

Hypertension in pregnancy (HP), including preeclampsia, is known to be a multifactorial disease. Recently, a Glu298Asp variant of the endothelial nitric oxide synthase gene (NOS3) was identified as being associated with coronary spasm and myocardial infarction, whereas it has been reported that endothelial nitric oxide synthase plays a role in HP. We therefore performed an association study of the Glu298Asp variant with HP among 152 HP patients and 335 normal pregnant control individuals, in the context of other risk factors before pregnancy. The frequency of the variant GA+AA NOS3 genotypes was significantly higher in the patients (0.23) than in the controls (0.12) (P < 0.01). Multivariate analysis revealed that family history of hypertension, TT genotype of the angiotensinogen gene (AGT), GA+AA NOS3 genotype, and prepregnancy body mass index > or = 24 were independent potent risk factors, after adjustment for maternal age and parity. The odds ratios of the factors were 2.7, 2.3, 2.2, and 2.1, respectively. Our results suggested that the Asp298 of NOS3 is a potent, independent risk factor for HP.

Topics: Angiotensinogen; Body Mass Index; Female; Genetic Variation; Genotype; Humans; Hypertension; Maternal Age; Multivariate Analysis; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Parity; Pedigree; Pre-Eclampsia; Pregnancy; Risk Factors

Identification of mutations contributing to the pathogenesis of essential hypertension performs to understand deeper consequences of developing pathophysiological changes, to value individual risk of hypertension in the preclinical stages and, regarding the observed genotype, to choose optimum therapy. The aim of the study was to prove the existence of difference in double genotype occurrence of polymorphic candidate genes between normotensive and hypertensive subjects.. A sample of Czech population (398 individuals), 192 normotensives (age of 45.87 +/- 3.0, BMI = 25.44 +/- 3.31 kg x m2) a 206 hypertensives (age of 48.71 +/- 8.42, BMI = 27.18 +/- 4.16 kg x m(-2)) was genotyped at angiotensinogen (AGT, M235T polymorphism, exon 2) and endothelin-1 (EDN-1, Taq I 8000 polymorphism, intron 4) genes by PCR methods. Experimental schedule was case-control. Chi2 and Fisher-exact test were used for statistical analyses. M-allele of angiotensinogen gene was associated with essential hypertension (p = 0.0111). Allele (-) alone at endothelin-1 gene was associated with essential hypertension with marginal significance (p = 0.0622). A significant loss of heterozygotes MT (M235 AGT) at homozygote (--) at endothelin-1 gene (p = 0.0025) as well as a significant increase of allele (-) of endothelin-1 gene at homozygote MM at angiotensinogen gene (p = 0.0034) were found. CONCLUSIONS; Interaction of two polymorphic genetic variants of angiotensinogen and endothelin-1 genes was found. From the pathophysiological point of view, the fact may be explained as a stream to compensate the influence of variability of other genes more causatively conditioning essential hypertension.

Topics: Adult; Angiotensinogen; Endothelin-1; Epistasis, Genetic; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Mutation; Polymorphism, Genetic

Development of experimental models by genetic manipulation in mice has proven to be very useful in determining the significance of particular genes in the development of or susceptibility to hypertension. Advances in molecular genetics, transgenic mouse technology, and physiological measurements in mice provided an opportunity to go a step further and develop models to analyze the physiological significance of specific gene variants potentially causing hypertension. In this report, we describe the development of a human angiotensinogen transgenic mouse model generated by targeting the human angiotensinogen gene upstream of the mouse HPRT locus by homologous recombination. The main benefit of this transgenic mouse model is that the human angiotensinogen gene is inserted into the mouse genome as a single copy at a predefined locus and in a specific orientation-a process that can be repeated utilizing other variants of this gene. We establish the validity of this approach by showing that the hAGT(hprt) mice have normal tissue- and cell-specific expression of the human angiotensinogen gene and normally produce and process the hAGT protein at physiological levels.

Topics: Angiotensinogen; Animals; Chromosome Mapping; Female; Gene Expression Regulation; Genetic Engineering; Genetic Variation; Genome; Humans; Hypertension; Hypoxanthine Phosphoribosyltransferase; Introns; Male; Mice; Mice, Transgenic; Organ Specificity; Recombination, Genetic; Reproducibility of Results; Stem Cells

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Topics: Adult; Alleles; Angiotensin II; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Female; Gene Deletion; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Sodium Chloride, Dietary

In order to investigate the candidate genes for essential hypertension(EH), the authors determined the frequencies of M235T allele variation in exon 2 of angiotensinogen(AGT) gene and angiotensin converting enzyme (ACE) gene in 95 normotensives and 87 hypertensives in Chinese.. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the variation AGT gene while PCR was used to determine ACE gene polymorphism.. T235 allele frequency was significantly higher in hypertensive patients than in controls (0.45 vs 0.33, P<0. 05) and it was noticeably higher in male hypertensives. The frequency of ACE D allele in the EH patients with family history was higher than that in controls(0.59 vs 0.41,P<0.05).. The variation of AGT gene was involved in the pathogenesis of hypertension, especially in male. The ACE D allele was associated with EH with family history.

Topics: Alleles; Angiotensinogen; Female; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic

In the human pregnant state a high molecular weight form of angiotensinogen (HMrA) is present in significant quantities in addition to the usual low molecular weight angiotensinogen (LMrA). In a previous study involving a small number of white women, it was found that women who had developed pregnancy-induced hypertension (PIH) had significantly higher levels of plasma HMrA. It has been determined that there are five isoforms of HMrA. The objectives of this study were to expand the previous study with the inclusion of black women and to determine which isoform(s) of plasma HMrA are elevated in PIH. Plasma LMrA and HMrA were quantitated in 24 normotensive pregnant women and 65 women with PIH. The PIH group had higher levels of HMrA and somewhat lower levels of LMrA than the normotensive group. The HMrA/LMrA ratio was elevated in 47% of the PIH group. The five isoforms of HMrA were quantitated in plasma from 10 white women with PIH, 10 black women with PIH, and 6 normotensive pregnant white women. Half of both the white and black women with PIH had an elevated HMrA/LMrA ratio. The relative proportion of the HMrA isomers was similar in all groups. These studies show that half the women with PIH have a distinct abnormality in their renin angiotensin system. Both white and black women show this abnormality. In those women who have an elevated total HMrA, all five isoforms of HMrA are equally elevated.

Topics: Angiotensinogen; Black People; Cohort Studies; Female; Humans; Hypertension; Molecular Weight; Pregnancy; Pregnancy Complications, Cardiovascular; Protein Isoforms; White People

Angiotensinogen (AGT) and angiotensin I-converting enzyme (ACE) are heritable traits, but whether the environmental context influences heritability has not been examined. Known genetic factors explain only a portion of variation in AGT and ACE, and levels of both proteins are influenced by the environment. The African diaspora provides an opportunity to compare these traits in genetically related populations in contrasting environments. As part of a study of the genetics of hypertension, we examined families that included 1449 Nigerians and 1147 African Americans. Body mass index (weight [kg]/height [m](2)) was 21 kg/m(2) in Nigeria and 29 kg/m(2) in the United States, which is consistent with a large environmental contrast. AGT was considerably higher among African Americans (1919 versus 1396, P<0.01), whereas ACE was higher in Nigerians (630 versus 517, P<0.01). A household effect was observed among the Nigerian families (spouse correlations 0.30 for AGT, 0.18 for ACE), and correlations among first-degree relatives were large (0.42 to 0. 51 and 0.36 to 0.38 for AGT and ACE, respectively). Among African Americans, the familial aggregations of AGT and ACE were very limited, and the familial correlation for AGT was not different from zero. Heritability was 77% for AGT and 67% for ACE in Nigeria and 18% for AGT and ACE in the United States. The familial patterns of body mass index and blood pressure were similar among both family sets. In conclusion, less familial aggregation was observed for AGT and ACE in the United States than in Nigeria, most likely reflecting a greater random individual environmental effect on these traits. Variation in heritability of traits could influence the power of epidemiological studies to identify genetic effects.

Topics: Adult; Angiotensinogen; Black People; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Nigeria; Peptidyl-Dipeptidase A; United States

To detect the variants in the core promoter region of angiotensinogen(AGT) gene, and to analyse the relationship between the AGT gene polymorphisms and essential hypertension in Tibetan population.. This is a case-control study consisting of 103 essential hypertensive subjects and 82 normotensive controls matched by age and sex. The variants in the AGT gene core promoter region were screened by polymerase chain reaction/single strand conformation polymorphism(PCR/SSCP) and further identified by automated sequencing. The A(-6)G polymorphism was determined in DNA extracted from leucocytes by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP).. (1) There were two different electrophoresis band patterns in PCR/SSCP analysis. PCR product direct sequencing showed that the two band patterns represented the AA, AC genotypes in the (-20) site of AGT gene respectively. The distribution of A(-20)C genotype was almost identical in essential hypertensive and normotensive groups (P>0.8). The A allele frequency was very high in both groups (control: 0.9175, hypertensive: 0.9124). (2)Distribution of genotype in the (-6) site of AGT gene was much different between the patient group and control group (P<0.005). The frequency of G allele was statistically higher in the patient group than in controls (0.374 vs 0.220, P<0.025).. Both Tibetan hypertensives and normotensives have higher frequency of A allele in AGT gene (-20) site. The higher frequency of G allele in the AGT gene (-6) site in Tibetan hypertension patients suggests that this allele may be the genetic susceptibility factor in the proceeding of essential hypertension in the Tibetan population.

Topics: Angiotensinogen; Case-Control Studies; Genetic Predisposition to Disease; Humans; Hypertension; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Tibet

Patients with insulin-dependent diabetes mellitus (IDDM) have a high risk of developing diabetic nephropathy, retinopathy and cardiovascular diseases. The contribution of gene polymorphisms of the renin angiotensin system to these complications is controversial and may differ among populations.. In 257 Dutch IDDM patients (188 with urinary albumin excretion (UAE) <30 mg/24 h), logistic regression analysis was used to study the relationships among, on the one hand, the insertion/deletion gene polymorphism of the angiotensin-converting enzyme gene (ACE-ID), the M235T gene polymorphism of the angiotensinogen gene (AGT-M235T), and the A1166C gene polymorphism of the angiotensin type 1 receptor gene (AT1-A1166C), and, on the other hand, UAE, retinopathy, hypertension, and coronary heart disease.. The T-allele of the AGT-M235T polymorphism was associated with an increased risk of an elevated UAE (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.06-8.61), but only when interaction with the D-allele of the ACE-ID polymorphism was considered. A previously described positive interaction between the T-allele of the AGT-M235T polymorphism and the D-allele of the ACE-ID polymorphism could not be confirmed. The T-allele was also associated with an increased risk of retinopathy (OR 3.89, 95% CI 1.79-8.47). The CC-genotype of the AT1-A1166C polymorphism was associated with hypertension (OR 3.58; 95% CI 1. 23-10.37).. In a Dutch IDDM population, including 69 patients with (incipient) diabetic nephropathy, the T-allele of the AGT-M235T polymorphism is associated with an elevated UAE and diabetic retinopathy and the CC-genotype of the AT1-A1166C polymorphism is associated with hypertension. A previously described interaction between the AGT-M235T and the ACE-ID polymorphisms could not be confirmed. Since the number of nephropathic patients in this study is small, these conclusions must be interpreted with caution.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Coronary Disease; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; DNA Transposable Elements; Gene Deletion; Humans; Hypertension; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

The reverse genetic approach, which examines genetic factors underlying the root of pathogenesis first, is a powerful tool to clarify the genetic cause of essential hypertension. Using the rat cross model, studies of the genetically hypertensive inbred rat model indicated several candidate loci on the rat chromosome responsible for blood pressure, but failed to identify the exact causal gene. Moreover, it was not certain that the rat data really reflect the human case. Thus, we shifted our focus to human genetics and carried out case control studies using the candidate gene approach. We mainly focused on gene components of the renin-angiotensin system as candidates, finding that angiotensinogen gene polymorphisms are genetic predisposing factors for hypertension. However, the results obtained from case-control studies using Japanese subjects were not consistent, suggesting that there was a problem in control sampling. In our recent study, we recruited more than 5,000 residents of an urban community as a general population and examined the association between genetic factors and their health status. Our results indicate that angiotensin-converting enzyme gene polymorphism is a male-specific genetic risk for essential hypertension. In light of our previous investigations, we present a discussion concerning the design of future studies of the genetics of hypertension.

Topics: Angiotensinogen; Animals; Asian People; Case-Control Studies; Chromosome Mapping; Genetic Predisposition to Disease; Humans; Hypertension; Japan; Polymorphism, Genetic; Rats; Renin-Angiotensin System

An association between preeclampsia (PE) and a common missense mutation of the methylenetetrahydrofolate reductase gene (MTHFR), a C to T substitution at nucleotide 677 (C677T), which converts an alanine to a valine residue, has been reported in Italian and Japanese populations. We examined 101 cases of hypertension in pregnancy (HP), including 73 cases of PE, and 215 normal pregnancy controls to confirm the association in Japanese women. No significant differences of the frequency of the T677 allele frequency or percentage of T677 homozygotes were detected among the various types of cases: HP (0.38, 12%, respectively), severe HP (0. 40, 12%), PE (0.38, 11%), severe PE (0.41, 11%), primiparous HP (0. 40, 12%), primiparous PE (0.44, 18%), nonelderly HP (0.39, 13%), nonelderly PE (0.40, 14%), nonobese HP (0.38, 12%), nonobese PE (0. 39, 10%), HP without homozygous T235 of the angiotensinogen gene (TT of AGT) (0.38, 15%), PE without TT of AGT (0.38, 15%), and controls (0.38, 15%). The results indicate that T677 of MTHFR may not be a risk factor for PE in Japanese population.

Topics: Adult; Alleles; Amino Acid Substitution; Angiotensinogen; Body Mass Index; DNA; Female; Gene Frequency; Humans; Hypertension; Japan; Maternal Age; Methylenetetrahydrofolate Reductase (NADPH2); Mutation; Oxidoreductases Acting on CH-NH Group Donors; Parity; Point Mutation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Severity of Illness Index; Statistics as Topic

The exact role of angiotensinogen (AGT) in vascular remodeling has yet to be determined. In the present study, we examined the effects of reducing plasma AGT by intravenous injections with antisense oligodeoxynucleotides (ODNs) against AGT targeted to the liver on vascular remodeling in spontaneously hypertensive rats (SHRs).. The ODNs against rat AGT were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method for regulating liver gene expression. Male SHRs (n = 18) and age-matched male Wistar- Kyoto (WKY) rats (n = 4) were used for this study. All animals were fed a standard rat diet throughout the experiment At 10 weeks of age, the SHRs were divided into three groups (n = 6); systolic blood pressure (SBP) was similar in each group. The control group received saline, the sense group was injected with the sense ODN complex and the antisense group was injected with the antisense ODN complex. WKY rats were fed for the same period of time. The ASOR-poly(L)lysine-ODN complex was injected into the tail veins twice a week.. At the end of the treatment, a reduction in AGT mRNA levels in the liver and plasma AGT was observed only in the animals injected with antisense ODNs. Antisense ODNs significantly reduced the plasma angiotensin II (Ang II) concentrations to levels similar to those observed in WKY rats. Antisense ODNs significantly reduced the SBP (180.7 +/- 4.4 mmHg) and media cross-sectional areas of the aorta (1.11 +/- 0.02 mm2), which were still larger than those seen in WKY rats (140.3 +/- 2.1 mmHg, 0.84 +/- 0.02 mm2), compared with the SHRs injected with sense ODNs (225.2 +/- 4.4 mmHg, 1.24 +/- 0.02 mm2) and control SHRs (223.7 +/- 4.8 mmHg, 1.25 +/- 0.02 mm2). The aortic angiotensin-converting enzyme (ACE) activity and collagen concentrations, which were significantly higher than those seen in WKY rats, did not significantly change among the SHR groups. The aortic AGT, ACE, angiotensin II type 1 (AT1) receptor and angiotensin II type 2 (AT2) receptor mRNA also did not significantly change among the SHR groups.. On the basis of these findings, plasma AGT is thus considered to play a role in the development of hypertrophy of smooth muscle in the aorta of SHRs, it is thought to have only a slight effect, however, on the remodeling of the matrix tissue when the suppression of hypertension is insufficient.

Topics: Angiotensin II; Angiotensinogen; Animals; Aorta; Blood Pressure; Blood Vessels; Collagen; Hypertension; Liver; Oligonucleotides, Antisense; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; RNA, Messenger; Tunica Media

The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin.. Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised.. Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Binding Sites; Callithrix; Crystallography, X-Ray; Drug Design; Humans; Hydrogen Bonding; Hypertension; Mice; Models, Molecular; Molecular Structure; Protease Inhibitors; Protein Binding; Protein Conformation; Renin; Structure-Activity Relationship; Substrate Specificity

The genetic analysis of hypertension has revealed complex and inconsistent results, making it difficult to draw clear conclusions regarding the impact of specific genes on blood pressure regulation in diverse human populations. Some of the confusion from previous studies is probably due to undetected gene-gene interactions. Instead of focusing on the effects of single genes on hypertension, we examined the effects of interactions of alleles at 4 candidate loci. Three of the loci are in the renin-angiotensin-system, angiotensinogen, ACE, and angiotensin II type 1 receptor, and they have been associated with hypertension in at least 1 previous study. The fourth locus studied is a previously undescribed locus, named FJ. In total, 7 polymorphic sites at these loci were analyzed for their association with hypertension in 51 normotensive and 126 hypertensive age-matched individuals. There were no significant differences between the 2 phenotypic classes with respect to either allele or genotype frequencies. However, when we tested for nonallelic associations (linkage disequilibrium), we found that of the 120 multilocus comparisons, 16 deviated significantly from random in the hypertensive class, but there were no significant deviations in the normotensive group. These findings suggest that genetic interactions between multiple loci rather than variants of a single gene underlie the genetic basis of hypertension in our study subjects. We hypothesize that such interactions may account for the inconsistent findings in previous studies because, unlike our study, prior studies almost always examined single-locus effects and did not consider the effects of variation at other potentially interacting loci.

Topics: Adolescent; Adult; Angiotensinogen; Chromosome Mapping; Genotype; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin

To evaluate the association between the angiotensinogen-6 polymorphism (AGT-6) and blood pressure levels.. Data were analysed from the first 4,322 subjects of the NHLBI Family Blood Pressure Program (FBPP), consisting of four networks (GenNet, GENOA, HyperGEN and SAPPHIRe), each conducting a multicentre observational family study to identify and characterize the genetic determinants of hypertension and blood pressure. The four studies use different designs (concordant sibpairs, discordant pairs, sibships, extended pedigrees), target different ethnic groups (Caucasian, African-American, Japanese, Chinese), and have different inclusion/exclusion criteria. However, the protocols and definitions were standardized across networks before data collection to allow maximum poolability.. Each network/racial group was analysed separately, using generalized linear models that accounted for the non-independence of family members and/or the confounding of anti-hypertensive medications as needed. The results were also pooled using a pre-planned meta-analysis technique.. AGT-6 was not significantly associated with blood pressure in any network/racial group. In the meta-analysis, the pooled effect of AGT-6 was small [hazard ratio = 1.10, 95% confidence interval (CI) = 0.99-1.22, P= 0.0647 for systolic; hazard ratio = 1.04, 95% CI = 0.89-1.21, P= 0.6383 for diastolic]. A post-hoc analysis restricting to subjects meeting JNC VI criteria for Stage I hypertension (blood pressure > 140/90 mmHg or medicated) showed a stronger statistically significant relationship for systolic blood pressure (hazard ratio = 1.44, 95% CI = 1.04-2.00, P= 0.0283).. AGT-6 has minimal to no effect on the inter-individual variation of blood pressure levels, and is at best a 'minor gene' for blood pressure in the population as a whole.

Topics: Adolescent; Adult; Angiotensinogen; Asian People; Black People; Blood Pressure; DNA; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Peptide Fragments; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Proportional Hazards Models; Taiwan; United States; White People

To evaluate the association between hypertensive cerebrovascular stroke and renin-angiotensin system gene polymorphism from Chinese cohort.. The polymorphisms of angiotensinogen(AGT) and angiotensin-converting enzyme(ACE) from 257 cases of simple essential hypertension(EH) and 218 cases of hypertensive stroke(131 hemorrhagic cases and 87 ischemic cases were detected by PCR-RFLP.. The frequencies of DD genotype and D allele of ACE gene in ischemic stroke were significantly higher than those in hemorrhagic stroke and EH, and the odds ratios(OR) of DD/II genotype were 3.25(2.20-4.79) and 2.87(2.03-4.06), while the OR of D/I allele were 1.83(1.38-2.43) and 1.69(1.27-2.24) respectively. Otherwise, there was no difference in frequency distribution of Met235Thr mutation polymorphism and DD+TT/non DD non TT combined among the three groups.. The I/D polymorphism of ACE gene may be one of the risk factors and susceptible genetic markers for ischemic stroke with essential hypertension in Chinese.

Topics: Angiotensinogen; Genotype; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Stroke

Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.

Topics: Adrenergic beta-Agonists; Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Body Weight; Cardiotonic Agents; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Heart; Humans; Hypertension; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardial Contraction; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Serine Proteinase Inhibitors; Vasodilator Agents

To examine the interaction of sodium intake with genetic variations of the angiotensinogen gene and hypertension.. A community-based case-reference study.. Two rural Japanese communities.. Non-overweight and non-drinking Japanese men and women: 229 hypertensives and 229 age-, sex- and community-matched normotensives aged 32 to 83 years.. Polymorphisms of the angiotensinogen gene detected by an allele-specific polymerase chain reaction. A priori hypothesis is individuals with 174M (threonine-to-methionine substitution) or 235T (methionine-to-threonine substitution) allelic variations may have an elevated risk of hypertension when they have a high sodium intake, estimated by 24-h urine collection and a dietary questionnaire.. The genotypic frequency of the haplotype including both the 174M and 235T alleles was higher among hypertensives than among normotensives (23 versus 14%, P= 0.02). The frequency of the 174M allele was specifically higher among hypertensives than normotensives (12 versus 7%, P=0.01), and the odds ratio of hypertension associated with the 174M (versus 174T) allele was 1.8 [95% confidence interval (CI) 1.1-3.0, P=0.01]. The frequency of the 235T allele did not vary between the two groups (80 versus 82%, P= 0.40). The relationship between the 174M allele and hypertension was more evident among persons who had higher urinary sodium excretion (> = 166 mmol/day) than those with lower excretion (< 166 mmol/day): odds ratio 2.5 (95% CI, 1.2-5.2), P=0.01 versus 1.5 (95% CI, 0.7-3.1), P= 0.31; P for interaction = 0.04, and this trend was primarily observed for early-onset hypertension (< 55 years at onset). A similar but nonsignificant association was observed when stratified using present and past sodium intake scores derived from questionnaires.. Angiotensinogen genotype may affect the development of early-onset hypertension among Japanese, particularly in those who have a high sodium intake.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Alcohol Drinking; Angiotensinogen; Asian People; Blood Pressure; Body Weight; Case-Control Studies; DNA Primers; Female; Gene Frequency; Haplotypes; Humans; Hypertension; Japan; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Rural Population; Sodium, Dietary

In addition to its haemodynamic effects, angiotensin II (AngII) is thought to contribute to the development of cardiac hypertrophy via its growth factor properties. The activation of mitogen-activated protein kinases (MAPK) is crucial for stimulating cardiac growth. Therefore, the present study aimed to determine whether the trophic effects of AngII and the AngII-induced haemodynamic load were associated with specific cardiac MAPK pathways during the development of hypertrophy. Methods The activation of the extracellular-signal-regulated kinase (ERK), the c-jun N-terminal kinase (JNK) and the p38 kinase was followed in the heart of normotensive and hypertensive transgenic mice with AngII-mediated cardiac hypertrophy. Secondly, we used physiological models of AngII-dependent and AngII-independent renovascular hypertension to study the activation of cardiac MAPK pathways during the development of hypertrophy.. In normotensive transgenic animals with AngII-induced cardiac hypertrophy, p38 activation is associated with the development of hypertrophy while ERK and JNK are modestly stimulated. In hypertensive transgenic mice, further activation of ERK and JNK is observed. Moreover, in the AngII-independent model of renovascular hypertension and cardiac hypertrophy, p38 is not activated while ERK and JNK are strongly stimulated. In contrast, in the AngII-dependent model, all three kinases are stimulated.. These data suggest that p38 activation is preferentially associated with the direct effects of AngII on cardiac cells, whereas stimulation of ERK and JNK occurs in association with AngII-induced mechanical stress.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Cells, Cultured; Enzyme Activation; Female; Hypertension; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Myocardium; Myosin Heavy Chains; p38 Mitogen-Activated Protein Kinases; Promoter Regions, Genetic; Renin; Stress, Mechanical; Transgenes; Vasoconstrictor Agents

The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Captopril; Collagen; Coronary Vessels; Hydralazine; Hypertension; Kidney Glomerulus; Male; Myocardium; Orchiectomy; Rats; Rats, Inbred SHR; Testosterone

A genetic linkage study of young-onset hypertension was performed on data from 59 nucleus families of Han Chinese residing in Taiwan. Thirty seven microsatellite markers near 18 hypertension candidate genes were genotyped. In a nonparametric identity-by-descent sibpair analysis, a positive linkage signal (defined as P<0.05) was found for four microsatellite markers, viz., D1S1612 (P=0.0162), D1S547 (P=0.0263), D8S 1145 (P= 0.0284), and D17S2193 (P=0.0256), which were located near genes for atrial natriuretic peptide (NPPA)/glucose transporter 5 (SLC2A5), angiotensinogen (AGT), lipoprotein lipase (LPL), and angiotensin-conveting enzyme (DCP1), respectively. Marker D5S1480 located near beta-2-adrenergic receptor (ADRB2) had a borderline P value (P=0.0785) for the positive signal. Comprehensive genotyping with further markers in these regions is underway to confirm whether these genes are linked to young-onset hypertension.

Topics: Adult; Age Factors; Age of Onset; Angiotensinogen; Atrial Natriuretic Factor; Genetic Linkage; Genetic Markers; Genotype; Glucose Transporter Type 5; Humans; Hypertension; Lipoprotein Lipase; Microsatellite Repeats; Monosaccharide Transport Proteins; Nuclear Family; Peptidyl-Dipeptidase A; Statistics, Nonparametric; Taiwan

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.

Topics: Angiotensinogen; Angiotensins; Creatinine; Genotype; Humans; Hypertension; Kidney; Kidney Function Tests; Polycystic Kidney Diseases; Polymorphism, Genetic

Even if the importance of angiotensinogen (AGT) gene has been known in gene targeting animals and humans genetic studies, its precise mechanism and the interaction among AGT gene variants, plasma AGT concentration and risk for hypertension remain uncertain. We examined whether AGT gene variants predispose to hypertension via an increase of plasma AGT concentration. Plasma AGT concentration was estimated from plasma angiotensin I which was cleaved by an excess amount of human renin and measured by RIA. Using 9 AGT gene variants which included new polymorphisms (G-152A and T+31C), we examined the association with hypertension and with plasma concentration by a case-control study. Haplotype analysis revealed that G-6A, T+31C and M235T polymorphisms were in absolute linkage disequilibrium and were associated with hypertension but not with plasma AGT level. On the other hand, -1074t;T235 haplotype was associated with an increase of AGT level but not with hypertension. In the haplotype analysis, only H3 haplotype frequency, which contained G-6, T+31 and M235 alleles, was significantly increased in normotensive subjects, suggesting that this haplotype is associated with a hypotensive effect. According to combined haplotype analysis of diallele and microsatellite markers, it remains a possibility that M235T, T+31C, G-6A, A-20C and G-1074T polymorphisms may play an important role in increased risk for essential hypertension. Our results suggest that the positive association between AGT polymorphism and hypertension is not simply explained by an increase of plasma AGT concentration.

Topics: Alleles; Angiotensin I; Angiotensinogen; Case-Control Studies; DNA; DNA Primers; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Radioimmunoassay; Reference Values

To study the renin-angiotensin system (RAS) involvement in the hormonal regulation of BP and blood volume and the relationship between angiotensinogen (AGT) was the sole preliminary acting materials in the RAS.. Population-based case-control study was conducted using PCR-RFLP techniques to explore the relationship between the M235T polymorphism of AGT and EH in Wangxin township, Jiading District of Shanghai.. The frequency of TT genotype in EH cases was significantly higher than in controls (42.8% and 33.0%). The odds ratio (OR) for those exposed to TT genotype was 3.61, comparing with MM genotype. It was suggested that TT genotype be the susceptible genotype of EH in Wangxin. The frequency of allele T in EH cases was 73.89%, significantly higher than that of 60.31% in controls. With the increase of allele T, the risk of EH also increased (P < 0.05). In EH cases, the BMI increased in the order of MM, MT and TT, and significant differences between the groups were observed.. TT genotype is the susceptible genotype of EH in Wangxin.

Topics: Aged; Alleles; Angiotensinogen; China; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Renin-Angiotensin System

To study the polymorphism of 5'-flanking region of angiotensinogen gene and relations to essential hyperfension.. The nucleotide sequence at position -155 to +25 of the 5'-flanking region in angiotensinogen gene of Han people in Chinese population was identified by applying PCR-single stranded conformational polymorphism(SSCP) and PCR-directed sequencing.. (1) The Han people carry an adenylate(A), instead of a cytidylate(C) at position -20 of the 5'-flanking region of AGT gene; (2) A new mutation T-->A at position -46 was detected and A-allele frequencies was similar in both hypertensives and normotensive controls.. The variant T-->A at position -46 of AGT gene was not associated with hypertension, but an adenylate (A) at position -20 of the 5'-flanking region of AGT gene. might be an genetic marker for Hans people.

Topics: 5' Flanking Region; Adult; Aged; Angiotensinogen; Asian People; China; Female; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Pedigree; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational

Linkage studies in the spontaneously hypertensive rat (SHR) have suggested that a gene or genes regulating blood pressure may exist on rat chromosome 19 in the vicinity of the angiotensinogen gene. To test this hypothesis, we measured blood pressure in SHR progenitor and congenic strains that are genetically identical except for a segment of chromosome 19 containing the angiotensinogen gene transferred from the normotensive Brown Norway (BN) strain. Transfer of this segment of chromosome 19 from the BN strain onto the genetic background of the SHR induced significant decreases in systolic and diastolic blood pressures in the recipient SHR chromosome 19 congenic strain. To test for differences in angiotensinogen gene expression between the congenic and progenitor strains, we measured angiotensinogen mRNA levels in a variety of tissues, including aorta, brain, kidney, and liver. We found no differences between the progenitor and congenic strains in the angiotensinogen coding sequence or in angiotensinogen expression that would account for the blood pressure differences between the strains. In addition, no significant differences in plasma levels of angiotensinogen or plasma renin activity were detected between the 2 strains. Thus, transfer of a segment of chromosome 19 containing angiotensinogen from the BN rat into the SHR induces a decrease in blood pressure without inducing any major changes in plasma angiotensinogen levels or plasma renin activity. These results indicate that the differential chromosome segment trapped in the SHR chromosome 19 congenic strain contains a quantitative trait locus that influences blood pressure in the SHR but that this blood pressure effect is not explained by differences in plasma angiotensinogen levels or angiotensinogen expression.

Topics: Angiotensinogen; Animals; Aorta; Blood Pressure; Brain; Chromosome Mapping; Female; Gene Expression Regulation; Gene Transfer Techniques; Genetic Linkage; Genetic Markers; Hypertension; Kidney; Liver; Male; Organ Specificity; Phenotype; Rats; Rats, Inbred BN; Rats, Inbred SHR; Renin; Transcription, Genetic

Hypertension and kidney damage in the double transgenic rat (dTGR) harboring both human renin and human angiotensinogen genes are dependent on the human components of the renin angiotensin system. We tested the hypothesis that monocyte infiltration and increased adhesion molecule expression are involved in the pathogenesis of kidney damage in dTGR. We also evaluated the effects of long-term angiotensin-converting enzyme (ACE) inhibition, AT1 blockade, and human renin inhibition on monocyte recruitment and inflammatory response in dTGR. Systolic blood pressure and 24-hour albuminuria were markedly increased in 7-week-old dTGR as compared with age-matched normotensive Sprague Dawley rats. We found a significant monocyte/macrophage infiltration in the renal perivascular space and increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the interstitium, intima, and adventitia of the small renal vessels. alphaLbeta2 integrin and alpha4beta1 integrin, the corresponding ligands for ICAM-1 and VCAM-1, were also found on infiltrating monocytes/macrophages. The expression of plasminogen activator inhibitor-1 and fibronectin in the kidneys of dTGR were increased and distributed similarly to ICAM-1. In 4-week-old dTGR, long-term treatment with ACE inhibition (cilazapril), AT1 receptor blockade (valsartan), and human renin inhibition (RO 65-7219) (each drug 10 mg/kg by gavage once a day for 3 weeks) completely prevented the development of albuminuria. However, only cilazapril and valsartan were able to decrease blood pressure to normotensive levels. Interestingly, the drugs were all equally effective in preventing monocyte/macrophage infiltration and the overexpression of adhesion molecules, plasminogen activator inhibitor-1, and fibronectin in the kidney. Our findings indicate that angiotensin II causes monocyte recruitment and vascular inflammatory response in the kidney by blood pressure-dependent and blood pressure-independent mechanisms. ACE inhibition, AT1 receptor blockade, and human renin inhibition all prevent monocyte/macrophage infiltration and increased adhesion molecule expression in the kidneys of dTGR.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Chemokine CCL2; Disease Models, Animal; Fibronectins; Gene Expression Regulation; Humans; Hypertension; Integrin alpha4beta1; Integrins; Intercellular Adhesion Molecule-1; Kidney; Lymphocyte Function-Associated Antigen-1; Macrophages; Male; Monocytes; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Receptors, Lymphocyte Homing; Renal Circulation; Renin; Vascular Cell Adhesion Molecule-1

The gene encoding angiotensinogen (AGT) has been widely studied as a candidate gene for hypertension. Most studies to date have relied on case-control analysis to test for an excess of AGT variants among hypertensive cases compared with normotensive controls. However, with this design, nothing guarantees that a positive finding is due to actual allelic association as opposed to an inappropriate control population. To avoid this difficulty in our study of essential hypertension in Anqing, China, we tested AGT variants using the transmission/disequilibrium test, a procedure that bypasses the need for a control sample by testing for excessive transmission of a genetic variant from parents heterozygous for that variant. We analyzed two AGT polymorphisms, M235T and T174M, which have been associated with essential hypertension in whites and Japanese, using data on 335 hypertensive subjects from 315 nuclear families and their parents. Except in the group of subjects younger than 25 years, M235 and T174 were the more frequently transmitted alleles. We found that 194 parents heterozygous for M235T transmitted M235 106 times (P=0.22) and that 102 parents heterozygous for T174M transmitted T174 60 times (P=0.09). Stratifying offspring by gender, M235 and T174 were transmitted 60 of 106 times (P=0.21) and 44 of 75 times (P=0.17), respectively, in men, and 46 of 88 times (P=0.75) and 16 of 27 times (P=0.44), respectively, in women. Our results were also negative in all age groups and for the affected offspring with blood pressure values >/=160/95 mm Hg. Thus, this study provides no evidence that either allele of M235T or T174M contributes to hypertension in this Chinese population.

Topics: Adult; Alleles; Angiotensinogen; China; Female; Heterozygote; Humans; Hypertension; Male; Polymorphism, Genetic

1. The role of the renin-angiotensin system (RAS) in cardiac hypertrophy and nephropathy was examined in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. 2. Tsukuba hypertensive mice were treated with 20 mg/kg per day lisinopril, 30 mg/kg per day hydralazine or nothing. Administration of drugs was performed for 6 months from 12 weeks of age; water intake and urine volume were measured and urine albumin excretion, heart to bodyweight ratio and the glomerulosclerosis index were examined. 3. Systolic blood pressure was significantly lowered by treatment with lisinopril and hydralazine. Urine volume, water intake and urinary albumin excretion were significantly decreased by lisinopril. When hydralazine was administered to THM, these parameters were transiently decreased, but eventually reached almost the same levels as those in the untreated group. The heart to bodyweight ratio was significantly decreased by lisinopril, but not by hydralazine. The glomerulosclerosis index was significantly lowered by lisinopril, but the index in the hydralazine group was not significantly different from that in the untreated group. 4. These results suggest that the RAS plays an important role in the progression of cardiac hypertrophy in THM. In addition, the RAS may also play an important role in the progression of nephropathy; however, this may also be partially regulated by elevated blood pressure in the short term.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Humans; Hydralazine; Hypertension; Kidney Diseases; Lisinopril; Mice; Mice, Inbred C57BL; Renin; Renin-Angiotensin System; Survival Rate

Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Arginine Vasopressin; Blood Pressure; Brain; Cerebral Ventricles; Diabetes Insipidus; Electrolytes; Exons; Hypertension; Hypotension; Injections, Intraventricular; Organ Specificity; Rats; Renin; RNA, Antisense; RNA, Messenger; Transcription, Genetic

The tissue renin-angiotensin system and extracellular matrix are involved in the cardiovascular hypertrophy and remodeling induced by hypertension. In this study, we examined the gene expression of the tissue renin-angiotensin system and fibronectin in inbred Dahl Iwai salt-sensitive and salt-resistant rats.. Eight pairs of 6-week-old male Dahl Iwai salt-sensitive and salt-resistant rats were fed either a low- or high-salt diet (0.3% or 8% NaCl, respectively) for 4 weeks. Activities of the circulating renin-angiotensin system were measured by radioimmunoassay and the gene expression of tissue angiotensinogen, the angiotensin II type 1 receptor (AT1) and fibronectin were analyzed by Northern blot analysis.. Salt loading significantly increased blood pressure and produced cardiovascular hypertrophy and nephrosclerosis in the salt-sensitive rats. Activities of the circulating renin-angiotensin system were lower in salt-sensitive rats than in salt-resistant rats fed the low-salt diet, and salt loading lowered these activities in salt-resistant rats but not in salt-sensitive rats. In salt-resistant rats, salt loading increased renal, cardiac and aortic angiotensinogen, AT1 and fibronectin messenger (m)RNA expression except for aortic fibronectin mRNA expression. In contrast, in the salt-sensitive rats, salt loading stimulated the expression of cardiac fibronectin and aortic angiotensinogen, AT1 and fibronectin mRNAs. Furthermore, the cardiac and aortic fibronectin mRNA levels in salt-sensitive rats were higher than those in salt-resistant rats when both strains were fed the high-salt diet.. These results demonstrate that the expression of tissue angiotensinogen, AT1 and fibronectin mRNAs is regulated differently in Dahl Iwai salt-sensitive and salt-resistant rats, and indicate that salt-mediated hypertension activates the cardiac fibronectin gene independently of the tissue renin-angiotensin system and stimulates the aortic fibronectin gene with activation of the tissue renin-angiotensin system.

Topics: Angiotensin I; Angiotensinogen; Animals; Aorta, Thoracic; Blood Pressure; Blotting, Northern; Fibronectins; Gene Expression; Hypertension; Male; Myocardium; Radioimmunoassay; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Sodium, Dietary

The angiotensinogen gene (AGT), which encodes the precursor of the vasoactive hormone angiotensin II, has been reported to be associated with hypertension in Caucasian and Japanese populations. We examined the relationship between two common molecular variants of AGT, T174M and M235T and blood pressure in two cohorts from the Anqing region of China. Cohort I (N = 794) consisted of families ascertained by either hypertensive or hypotensive siblings; and Cohort II (N = 761) represented a collection of randomly selected families.. Blood pressure was measured according to standard protocols, and information on age, sex, body mass index, alcohol consumption, and cigarette smoking was collected by trained interviewers using standardized questionnaires. The association of AGT genotypes and blood pressure was examined in multivariate linear regression models, with adjustment for potential intrafamilial correlations. The respective T and M allele frequencies for T174M were 0.93 and 0.07, and 0.80 and 0.20 for M235T among the parents for randomly selected families. All the analyses were conducted after exclusion of individuals currently under antihypertensive medication.. In the pooled analysis of the two cohorts, neither the T174M nor the M235T polymorphism was significantly associated with variations of blood pressure assuming a recessive (T174M: p = 0.73 and 0.61; M235T: p = 0.99 and 0.24; for SBP and DBP), dominant (T174M: p = 0.54 and 0.72; M235T: p = 0.79 and 0.12; for SBP and DBP), or additive (T174M: p = 0.52 and 0.67, M235T: p = 0.91 and 0.11; for SBP and DBP) model. Likewise, no statistically significant association was detected when the two cohorts were analyzed separately. The logistic regression analysis of hypertension also failed to reveal any association with these markers.. In summary, our analyses suggest that the molecular variants of AGT may not be associated with variations of blood pressure in this rural Chinese population.

Topics: Adolescent; Adult; Alleles; Angiotensinogen; Blood Pressure; Chi-Square Distribution; Female; Gene Frequency; Genotype; Humans; Hypertension; Hypotension; Male; Middle Aged; Polymorphism, Genetic; Prevalence; Regression Analysis

A missense gene mutation with methione-to-threonine amino acid substitution at codon 235 (M235T) of angiotensinogen (AGT) has been associated with higher plasma AGT levels and may influence the pathogenesis of cardiac hypertrophy and atherosclerosis. This study was undertaken to investigate the relationship of the M235T polymorphism of the AGT gene with left ventricular mass (LVM) and carotid intima-media thickness (IMT) in 175 Chinese patients with hypertension. The M235T mutation was detected by a mispairing primer method to create a BstUI restriction site in the polymerase chain reaction. The LVM was calculated with M-mode echocardiographic measures of the left ventricle. The IMT was measured in the common carotid and carotid bifurcation by B-mode ultrasound. Patients with the TT genotype (n = 106) were found to have significantly greater LVM index than those with the MM (n = 32) and MT (n = 37) genotypes (129.2 +/- 34.3 v 112.5 +/- 38.3 and 107.4 +/- 30.0 g/m2, P = .002), but the carotid IMT showed insignificant differences among three genotypic groups (1.320 +/- 0.703, 1.349 +/- 0.777, and 1.309 +/- 0.797 mm, P = .97). The M235T polymorphism (P = .004) was a significant predictor for LVM on multiple regression analysis, controlling all the potential confounding factors including age (P = .04), gender (P = .000), body mass index (P = .000), and so on, but the carotid IMT correlated only with age (P = .000), smoking (P = .02), and tissue plasminogen activator antigen (P = .02). These results indicated that the TT genotype of the AGT gene could be considered a risk factor for the development of cardiac hypertrophy, but not for carotid atherosclerosis in the hypertensive population.

Topics: Amino Acid Substitution; Angiotensinogen; Arteriosclerosis; Blood Flow Velocity; Blood Pressure; Carotid Arteries; Carotid Artery Diseases; DNA; DNA Primers; Echocardiography, Doppler, Pulsed; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Mutation, Missense; Polymerase Chain Reaction; Polymorphism, Genetic; Predictive Value of Tests; Ultrasonography, Doppler, Duplex

It has been reported that intracerebroventricularly injected antisense oligonucleotide to angiotensinogen reduces arterial pressure in spontaneously hypertensive rats (SHR), but the mechanism and the sites of action remain unclear. In the present study, we examined whether injection of antisense oligonucleotide to angiotensinogen into the paraventricular hypothalamic nucleus (PVN) would influence arterial pressure and vasopressin release. For this purpose, 12-week-old male SHR were cannulated into the bilateral PVN. One week later, we injected antisense or sense oligonucleotide to angiotensinogen into the bilateral PVN (0.2 nmol/200 nl each side). After 24 h, we directly monitored arterial pressure, and then took blood samples to measure plasma vasopressin, catecholamines and renin activity. Mean arterial pressure did not change in either group (from 144+/-3 to 154+/-4 mmHg for the antisense oligonucleotide group, n=11; from 147+/-4 to 156+/-3 mmHg for the sense oligonucleotide group, n=11). Antisense oligonucleotide attenuated vasopressin release compared with sense oligonucleotide (1.30+/-0.28 vs. 3.29+/-0.60 pg/ml, respectively, P<0.01). Plasma catecholamines also decreased in the antisense oligonucleotide group compared with the sense oligonucleotide group. However, the plasma renin activity did not differ between the groups. In the additional experiment, we examined the neurohormonal and cardiovascular effects of intracerebroventricularly injected antisense oligonucleotide to angiotensinogen in SHR. Mean arterial pressure, plasma vasopressin and plasma norepinephrine were significantly lower in the antisense oligonucleotide group than in the sense oligonucleotide group. These results suggest that angiotensinogen in PVN plays important roles in vasopressin release and sympathetic nerve activity, but may not contribute to the maintenance of arterial pressure in SHR.

Topics: Angiotensinogen; Animals; Hypertension; Injections, Intraventricular; Male; Oligonucleotides; Oligonucleotides, Antisense; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred SHR; Secretory Rate; Vasopressins

Previous studies of hypertension in humans and experimental animal models have identified a number of candidate genes that have since been implicated as possibly contributing to essential hypertension. Among them are the genes encoding angiotensinogen, renin, the beta- and gamma-subunits of the epithelial sodium channel (beta/gamma-ENaC), alpha-adducin, and kallikrein (KLK). To examine the role of possible contribution of these genes in ethnic Chinese, as well as the epistatic interaction among them, we studied a large cohort of hypertensive sib pairs from China. DNA samples from 310 concordant affected sibling pairs with hypertension were tested for linkage with the use of excess allele-sharing algorithms based on genotyping with highly informative GT-repeat microsatellite markers localized in the immediate vicinity of the genes encoding angiotensinogen, renin, beta- and gamma-ENaC, alpha-adducin, and KLK. Affected sib pair analysis conducted according to 3 different methods (Statistical Analysis for Genetic Epidemiology [S.A.G.E. ]/SIBPAL, MAPMAKER/SIBS, and affected pedigree member [APM] methods) revealed no evidence for linkage of any of these genes to primary hypertension in the population studied. Moreover, 2-locus sib pair linkage analyses to test for gene-gene interactions among each possible pair of candidate genes failed to yield any statistically significant results. Our findings provide no support for a significant contribution of the angiotensinogen, renin, beta/gamma-ENaC, alpha-adducin, or KLK genes, alone or in concert, to the pathogenesis of essential hypertension among Chinese. Our results emphasize the possible role of ethnic differences for complex disease genetics, as well as the need for large, well-characterized investigations.

Topics: Angiotensinogen; Animals; Calmodulin-Binding Proteins; China; Chromosome Mapping; Cohort Studies; Epithelial Sodium Channels; Ethnicity; Genetic Markers; Humans; Hypertension; Kallikreins; Microsatellite Repeats; Models, Genetic; Nuclear Family; Pedigree; Renin; Sodium Channels

Although the angiotensinogen gene is a possible candidate as a determinant of hypertension, the molecular mechanisms of tissue angiotensinogen gene regulation have yet to be clarified. We identified essential transcription regulators of angiotensinogen production in the central nervous system using synthetic double-stranded oligodeoxynucleotides (ODNs) as "decoy" cis elements to block the binding of nuclear factors to promoter regions of the targeted gene. Using a gel mobility shift assay, angiotensinogen gene-activating element (AGE) 2 binding protein was detected in the brain nuclear extracts of both spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs). Importantly, the binding activity of AGE 2 and angiotensinogen mRNA level were significantly higher in the brain of SHRs than in that of WKYs. Using the decoy approach, we demonstrated a significant decrease in the blood pressure of SHRs by transfection of AGE 2 decoy, but not mismatched, ODNs into the lateral cerebroventricle, accompanied by a significant decrease in brain angiotensinogen concentration and mRNA, and angiotensin II level. That these effects, demonstrated herein, are due to central effects is confirmed by the fact that no changes in circulating levels of angiotensinogen or angiotensin II concentrations were observed. Notably, AGE 2 decoy ODNs did not decrease the blood pressure of WKYs. We conclude that the abnormal expression of AGE 2 binding protein in the central nervous system plays a crucial role in high blood pressure of a genetically hypertensive rat model.

Topics: Angiotensinogen; Animals; Blood Pressure; Brain; Carrier Proteins; Cerebrovascular Circulation; Gene Expression Regulation; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

It has been reported the association between M235T angiotensinogen (AGT) and I/D angiotensin converting enzyme (ACE) gene polymorphisms and hypertension and other cardiovascular risk factors. However there are few data about Spanish population. So that we have studied the relationship among the aforementioned polymorphisms and hypertension and the possibility of association between any polymorphism and a worse cardiovascular risk profile.. 251 hypertensive and 245 control normotensive subjects were studied. The M235T AGT and the I/D ACE gene polymorphisms were determined by polymerase chain reaction (PCR). Family and personal history of cardiovascular disease, lipoprotein profile, microalbuminuria and left ventricular hypertrophy (LVH) by Sokolow index were analyzed in hypertensive patients.. The distribution of the different polymorphisms was similar among hypertensive and normotensive subjects. There was not any relationship among AGT nor ACE genotypes and target organ damage. The II ACE genotype was associated with higher lipoprotein (a) (Lp[a]) levels and greater cerebrovascular disease family history and the MT AGT genotype with lower total cholesterol (TC) and triglycerides (TG) levels.. In our study there was not any relationship between arterial hypertension and M235T AGT or I/D ACE gene polymorphisms. None specific genotype was associated with worse cardiovascular risk profile. The II ACE genotype was a predictor of cerebrovascular disease risk through higher levels of Lp(a) and the MT AGT genotype was associated with a better lipid profile.

Topics: Adult; Angiotensinogen; Cardiovascular Diseases; DNA Probes; Female; Genotype; Humans; Hypertension; Lipids; Male; Middle Aged; Molecular Sequence Data; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors

The contribution of genetic factors to hypertension in pregnancy, including pre-eclampsia, has been well documented. The association with a common molecular variant of the angiotensinogen (AGT) gene, in which methionine (M235) is substituted for threonine (T235) at residue 235, has been reported in both Caucasians and Japanese. In the present study, we examined 115 cases of pure type of hypertension in pregnancy (PHP) and 381 normal pregnant controls in order to look for subgroups in which the AGT gene is the major factor in the PHP pathogenesis. By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls. These results are discordant with those reported for Caucasian subjects where only a group of preeclamptic primigravidae was associated with the AGT variant, possibly indicating the existence of a racial difference. We also found that the variant frequency was significantly higher in the PHP subgroup with maternal age of 20-34 years (0.93) than in a subgroup of multigravid PHP patients age 35 years or older (0.77, P < 0.05) or in normal controls of age 20-34 years (0.76, P < 0.001). The result indicates that the AGT variant plays a significant role in hypertension in the age group 20-34 years.

Topics: Adult; Age Factors; Alleles; Angiotensinogen; Asian People; Base Sequence; Case-Control Studies; DNA Primers; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; Japan; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

Molecular variants of the angiotensinogen gene, a key component of the renin-angiotensin system, are considered genetic risk factors for primary hypertension. A relation between the angiotensinogen gene locus and hypertension has been found in whites, Japanese, and African Caribbeans but not in Chinese. The lack of a consistent association between M235T polymorphism at exon 2 and hypertension has suggested that another site in linkage disequilibrium with M235T is the causal mutation. We studied the relations among plasma angiotensinogen concentrations, blood pressure, related clinical variables, and mutations of the 5' upstream core promoter region of the human angiotensinogen gene in 274 subjects recruited from our outpatient clinic. We confirmed that plasma angiotensinogen concentration was significantly correlated with A-20C mutation and percent body fat and found that systolic and diastolic blood pressures were significantly correlated with G-6A and T+68C mutations. These results suggest that mutations near the transcription start site may be associated with increased blood pressure.

Topics: Angiotensinogen; Blood Pressure; Female; Haplotypes; Humans; Hypertension; Introns; Linear Models; Male; Middle Aged; Point Mutation; Polymorphism, Genetic; Transcription, Genetic

In a hospital cohort study, we examined whether or not ACE (Angiotensin-I converting enzyme) and AGT (Angiotensinogen) gene polymorphisms were associated with the development of nephropathy in long-term Japanese insulin-dependent diabetes mellitus (IDDM) patients with or without proliferative retinopathy, and whether or not the polymorphisms were associated with an arteriosclerotic family history in first degree relatives of the patients. A total of 201 patients with IDDM for more than 10 years and 159 patients with IDDM for more than 15 years were randomly selected in our hospital. All patients received uniform diabetes management and were divided into three groups, no nephropathy, incipient nephropathy and clinical nephropathy groups. There were no differences in clinical characteristics excluding urinary albumin to creatinine ratio and systolic blood pressure between the three groups. ACE I/D polymorphism was related to plasma ACE activity, but there were no associations between ACE I/D polymorphism and the development of diabetic nephropathy, nor was renal deterioration observed in patients with proliferative retinopathy even in those with a history of diabetes for more than 15 years. The AGT polymorphism did not have an additive effect on the association between ACE polymorphism and the development of diabetic nephropathy in patients with or without retinopathy. Development of diabetic nephropathy in the patients with or without proliferative retinopathy did not result in ACE or AGT polymorphisms. On the other hand, the ACE DD genotype was associated with a family history of ischemic heart disease in first degree relatives (X2 score = 9.04, P < 0.05). ACE and AGT gene polymorphisms may not play a role in the protective or accelerative effect against the development of diabetic nephropathy in the patients with or without proliferative retinopathy, but ACE gene polymorphism might be related to an arteriosclerotic family history in Japanese IDDM patients.

Topics: Adult; Albuminuria; Angiotensinogen; Blood Pressure; Cohort Studies; Creatine; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; DNA; Female; Glycated Hemoglobin; Humans; Hypertension; Japan; Male; Myocardial Ischemia; Ophthalmoscopy; Peptidyl-Dipeptidase A; Point Mutation; Polymorphism, Genetic; Renin-Angiotensin System

Earlier epidemiologic studies have yielded inconsistent results on the extent and timing of the blood pressure (BP) increase in offspring of hypertensive parents. We hypothesized that a familial influence on the BP of the offspring exists from birth on, but becomes significant only later in childhood. We studied the influence of familial occurrence of hypertension on the BP of 3596 children aged 6 to 18 years during a 6-year follow-up. In addition, we examined the possible associations of BP variations with polymorphisms of two candidate genes for hypertension, ie, those coding for the angiotensin converting enzyme (ACE) and those coding for angiotensinogen. A positive family history of hypertension was reflected as the occurrence of higher systolic BP values from the age of 9 years and upward among the females and from the age of 12 years and upward among the males. The mean differences in BP varied from 3.2 to 5.8 mm Hg (systolic) and 2.1 to 5.9 mm Hg (diastolic) between the female offspring of normotensive and hypertensive parents and grandparents. The systolic BP values were significantly higher among females with a hypertensive history in two generations in comparison with females from normotensive families. Among the male offspring of hypertensive and normotensive families, the BP differences were inconsistent. The deletion/deletion males had higher systolic BP values than those with other ACE genotypes. In contrast, variation at the angiotensinogen gene locus was not significantly associated with BP. We conclude that parental history of hypertension is a risk factor for high blood pressure among the offspring from the ages of 9 to 12 years and upward, and hypertension within two generations may enhance this effect. Although the common genetic variation of ACE may influence blood pressure in male children and adolescents, our data do not suggest a role for the common variation of the angiotensinogen gene as a BP regulator during childhood.

Topics: Adolescent; Adult; Angiotensinogen; Blood Pressure; Child; Child, Preschool; DNA; DNA Primers; DNA Transposable Elements; Female; Follow-Up Studies; Gene Deletion; Genetic Code; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Minisatellite Repeats; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Retrospective Studies

Recently, a novel mutation in the promoter region of the angiotensinogen gene that involves the presence of an adenine instead of a guanine 6 bp upstream from the transcription initiation site (A(-6)G) has been shown to induce an increase in gene transcription. The aim of this study was to determine the prevalence of the A(-6)G mutation in essential hypertensive patients and to correlate it with aldosterone and renin activity levels. We studied 191 hypertensives. We measured levels of aldosterone (plasma and urinary) and plasma renin activity. We determined the variants A and G using a mutagenically separated polymerase chain reaction technique. In 191 hypertensives, the A variant was detected in 266 of 382 (69.6%) and the G variant in 116 of 382 alleles (30.4%). Plasma aldosterone was significantly higher in patients homozygous for AA than in those homozygous for GG (369+/-208 versus 246+/-142 pmol/L). Urinary aldosterone was significantly higher in homozygous AA than in AG or GG patients (62.4+/-39.4 versus 50.8+/-25.2 and 37.4+/-22.3 nmol/d, respectively). When the patients were grouped according to the presence or absence of the A allele, the aldosterone levels and the plasma aldosterone/plasma renin activity ratio were significantly higher in patients with the A allele. The presence of the A variant was associated with higher levels of aldosterone. These results suggest that the presence of the A variant could determine the appearance of arterial hypertension through higher transcription activity of the angiotensinogen gene and concomitant aldosterone production.

Topics: Aged; Aldosterone; Angiotensinogen; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Point Mutation; Promoter Regions, Genetic

Linkage with essential hypertension has been claimed for a microsatellite marker near the angiotensinogen gene (AGT; chromosome 1q42), as has association for the AGT variants M235T, G(-6)A and A(-20)C. To more rigorously evaluate AGT as a candidate gene for hypertension we performed sibpair analysis with multiple microsatellite markers surrounding this locus and using more sophisticated analysis programs. We also performed an association study of the AGT variants in unrelated subjects with a strong family history (two affected parents). For the linkage study, single and multiplex polymerase chain reaction (PCRs) and automated genescan analysis were conducted on DNA from 175 Australian Anglo-Celtic Caucasian hypertensives for the following markers: D1S2880-(2.1 cM)-D1S213-(2.8 cM)-D1S251-(6.5 cM)-AGT-(2.0 cM) -D1S235. Statistical evaluation of genotype data by nonparametric methods resulted in the following scores: Single-point analysis - SPLINK, P > 0.18; APM method, P > 0.25; ASPEX, MLOD < 0.28; SIB-PAIR, P > 0. 24; Multipoint analysis - MAPMAKER/SIBS, MLOD < 0.24; GENEHUNTER, P > 0.35. Exclusion scores of Lod -4.1 to -5.1 were obtained for these markers using MAPMAKER/SIBS for a lambda(s) of 1.6. The association study of G(-6)A, A(-20)C and M235T variants in 111 hypertensives with strong family history and 190 normotensives with no family history showed significant linkage disequilibrium between particular haplotypes, but we could find no association with hypertension. The present study therefore excludes AGT in the etiology of hypertension, at least in the population of Australian Anglo-Celtic Caucasians studied.

Topics: Adult; Aged; Alleles; Angiotensinogen; Australia; Family Health; Female; Gene Frequency; Genetic Linkage; Genotype; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Microsatellite Repeats; Middle Aged; Nuclear Family; Polymorphism, Genetic; White People

Topics: Angiotensinogen; Animals; Gene Expression Regulation, Enzymologic; Humans; Hypertension; Polymorphism, Genetic; Promoter Regions, Genetic; Transcription Factors

Recent developments in molecular biological techniques allowed us to examine the genetic risk factors responsible for essential hypertension. The candidate gene approach revealed that several gene polymorphisms increase the relative risk for hypertension. Most genetic studies, however, examined only young subjects but not elderly ones. To examine the importance of gene polymorphisms in elderly hypertension, we carried out a case-control study and compared the odds ratio for hypertension between young (< 60) and elderly (> or = 60) subjects. The participants of this study were recruited from the outpatients of Osaka University Medical School with informed consent. We examined the following polymorphisms as candidates: the angiotensinogen (AGT/M235T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 (AT1/A1166C) and type 2 (AT2/C3123A) receptors, alpha-adducin (adducin/Gly460Trp), methylenetetrahydrofolate reductase (MTHHR/C677T), and apolipoprotein (apoE/epsilon 4, apoE/T-491A). In young subjects, the AGT/T235 allele significantly increased the odds ratio for hypertension but not in elderly subjects. In young males, the AT2/A3123 allele was also associated with hypertension but not in females or in elderly subjects. Other associations between polymorphism and hypertension did not reach a significant level. To sum up, it was revealed that some polymorphisms increase the susceptibility for hypertension but others do not, which suggests that there is heterogeneity in the genetic involvement of polymorphism due to aging.

Topics: Aged; Angiotensin II; Angiotensinogen; Apolipoproteins; Case-Control Studies; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

To clarify risk factors for the progression of microalbuminuria in Japanese type 2 diabetic patients, the longitudinal study for 10 years was conducted on 67 outpatients with type 2 diabetes, who had shown no overt proteinuria at baseline. The urinary albumin index (UAI) has been determined based on the mean of at least two random urine samples each year. Categories were defined as normoalbuminuria (UAI < 30.0 mg/g x Cr.), microalbuminuria (30.0 < or = UAI < 300.0), and macroalbuminuria (UAI > or = 300.0). Progression was defined as worsening of the category and/or more than doubling of the baseline UAI value. Multiple logistic regression analysis was performed using age, duration of diabetes, HbA1c, blood pressure, BMI, serum lipids, smoking habits, and alcohol consumption as independent variables and the progression of microalbuminuria as a dependent variable. Age and HbA1c were estimated as significant and independent variables. Furthermore, genetic polymorphisms of angiotensin I-converting enzyme (ACE) and angiotensinogen were analyzed to evaluate the genetic contribution. The D/D genotype of ACE was significantly more common in progressors than in non-progressors. These results suggest that glycemic control and age are important risk factors and the D/D genotype of ACE acts as a risk factor for the progression of microalbuminuria in Japanese type 2 diabetic patients.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Genotype; Humans; Hypertension; Japan; Longitudinal Studies; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

Familial clustering of altered albumin excretion and nephropathy risk has been described in both type 1 and type 2 diabetes; moreover, an association of micro-macroalbuminuria and diabetic retinopathy has been recently reported in a large number of white families with type 2 diabetes. Conflicting reports, mainly comparing affected with unaffected unrelated subjects, have suggested a possible role of some genotypes of the renin-angiotensin system in conferring nephropathy risk in type 2 diabetes. To examine the role of genetic factors in influencing albuminuria in families, we studied the relation of angiotensin-converting enzymes (ACE) and angiotensinogen (AGN) genotypes with albumin excretion rate in a population of affected siblings of type 2 diabetic probands. We determined ACE insertion/deletion polymorphism and two polymorphisms of the AGN gene (T174M and M235T) in 160 families with at least one affected member. Defining proband as the patient with the longest known duration of diabetes, we compared the allelic distribution in diabetic probands with and without altered albumin excretion and in their siblings. Allelic distribution of these polymorphisms was similar in the two groups of probands, as well as in their siblings. Identity-by-State (IBS) analysis showed a link between AGN locus and arterial hypertension in these siblings, which was independent from the degree of renal involvement. Thus, our findings suggest that in white families with type 2 diabetes, there is no linkage between the degree of albumin excretion and ACE and AGN polymorphisms, whereas the latter is related to arterial hypertension, as previously found in patients without diabetes but with essential hypertension.

Topics: Albuminuria; Alleles; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Genetic Linkage; Genotype; Humans; Hypertension; Italy; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

Angiotensinogen (ANG) is the specific substrate of the renin-angiotensin system, a major participant in blood pressure control. We have identified a natural mutation at the -30 amino acid position of the angiotensinogen signal peptide, in which an arginine is replaced by a proline (R-30P). Heterozygous individuals with R-30P showed a tendency to lowered plasma angiotensinogen level (1563 ng of ANG I/ml (range 1129-1941)) compared with normal individuals in the family (1892 ng of ANG I/ml (range 1603-2072)). Human angiotensinogen mRNA has two in-phase translation initiation codons (AUG) starting upstream 39 and 66 nucleotides from the cap site. R-30P occurs in a cluster of basic residues adjacent to the first AUG codon that may affect intracellular sorting of the nascent protein. Pulse-chase experiments in transiently transfected cultured cells revealed that the R-30P mutation was associated with reduced amounts of both intra- and extracellular protein. In a cell-free system, we found that two forms of native angiotensinogen were generated by alternative initiation of translation at either AUG codon. Alteration of either the first or second AUG codons abolished the synthesis of the longer and the shorter form of native angiotensinogen, respectively. Furthermore, the rate of secretion of the shorter form was lower than that of the longer form. By transplanting angiotensinogen signal peptide onto green fluorescence protein, however, we found that both forms of the signal peptide could target green fluorescence protein, normally localized in the cytoplasm, to the secretory pathway. Although the R-30P mutation may not affect intracellular sorting of angiotensinogen in a qualitative manner, it leads to a quantitative reduction in the net secretion of mature angiotensinogen through decreased translocation or increased residence time in the endoplasmic reticulum.

Topics: Amino Acid Sequence; Angiotensinogen; Animals; Base Sequence; Codon; COS Cells; Female; Humans; Hypertension; Male; Molecular Sequence Data; Pedigree; Point Mutation; Polymorphism, Single-Stranded Conformational; Protein Biosynthesis; Recombinant Proteins; RNA, Messenger; Transfection

Angiotensinogen (AGT) has been linked to hypertension. Because there are no direct inhibitors of AGT, we have developed antisense (AS) inhibition of AGT mRNA delivered in an adeno-associated virus (AAV)-based plasmid vector. This plasmid, driven by the cytomegalovirus promoter, contains a green fluorescent protein reporter gene and AS cDNA for rat AGT. Transfection of the plasmid into rat hepatoma cells brought a strong expression of the transgenes and a significant reduction in the level of AGT. In the in vivo study, naked plasmid DNA was intravenously injected into adult spontaneously hypertensive rats at different doses (0.6, 1.5, and 3 mg/kg). Expression of AGT AS mRNA was present in liver and heart, and it lasted longer in the liver. All three doses produced a significant decrease in blood pressure (BP). BP decreased for 2, 4, and 6 days, respectively. The lowest dose decreased BP by 12 +/- 3.0 mmHg, whereas the higher doses decreased BP by up to 22.5 +/- 5.2 mmHg compared with the control rats injected with saline (P < 0.01). The injection of the plasmid with liposomes produced a more profound and longer reduction (8 days) in BP. Consistent changes in plasma AGT level were observed. Sense plasmid had no effect. No liver toxicity was observed after injection of AS plasmid with or without liposomes. Our results suggest that the systemic delivery of AS against AGT mRNA by AAV-based plasmid vector, especially with liposomes, may have potential for gene therapy of hypertension and that further studies with the plasmid packaged into a recombinant AAV vector for a longer-lasting AS effect are warranted.

Topics: Angiotensinogen; Animals; Blood Pressure; Carcinoma, Hepatocellular; Cytomegalovirus; Dependovirus; Genes, Reporter; Genetic Vectors; Green Fluorescent Proteins; Hypertension; Injections, Intravenous; Liver; Liver Neoplasms; Luminescent Proteins; Male; Myocardium; Oligodeoxyribonucleotides, Antisense; Promoter Regions, Genetic; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Systole; Time Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured

To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population.. The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study.. The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension.. The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.

Topics: Aged; Aging; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To dissect the genetic pathway of hypertension, we measured angiotensinogen in 685 members of 186 families recruited from a rural community in southwest Nigeria. Commingling and segregation analyses were carried out. A mixture of two and/or three distributions fits the data significantly better than a single distribution in commingling analysis, suggesting a major gene effect. Segregation analysis confirmed that a recessive major gene model for low values of angiotensinogen provides the best fit to the data and about 13% of the variance was due to the recessive gene segregation.

Topics: Adolescent; Adult; Angiotensinogen; Blood Pressure; Female; Genes, Recessive; Humans; Hypertension; Male; Middle Aged; Models, Genetic; Nigeria; Rural Population

We studied the role of angiotensin II in pressure overload-induced B-type natriuretic peptide (BNP) gene expression by using a double transgenic rat (dTGR) model, in which transgenic rats for the human angiotensinogen and renin genes are crossed. Pressure overload produced by [Arg8]-vasopressin (AVP) infusion (i.v., 0.05 microg/kg/min for 2 h) in conscious, chronically instrumented rats, resulted in a significantly greater increase in BNP mRNA levels in the left atrium of the dTGR rats than in Sprague-Dawley (SD) control rats (3.6- vs 1.6-fold, p < 0.05), while in the left ventricle there was no significant difference between the strains. In dTGR rats, the early activation of the BNP gene expression was associated with a decrease in immunoreactive BNP levels in the atrium (27.5%, p < 0.05), but not in the ventricle. In SD rats, ir-BNP levels did not change significantly in either atria or ventricles in response to AVP infusion. These results show that the pressure overload-induced activation of BNP gene expression differs between atrial and ventricular myocytes in the dTGR model of experimental hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Gene Expression; Heart Atria; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

We tested the hypothesis that the tissue-specific intrarenal renin-angiotensin system (RAS) can participate in the regulation of blood pressure independently of its endocrine counterpart, by generating two transgenic models that differ in their tissue-specific expression of human angiotensinogen (AGT). Human AGT expression was driven by its endogenous promoter in the systemic model and by the kidney androgen-regulated protein promoter in the kidney-specific model. Using molecular, biochemical, and physiological measurements, we demonstrate that human AGT mRNA and protein are restricted to the kidney in the kidney-specific model. Plasma ANG II was elevated in the systemic model but not in the kidney-specific model. Nevertheless, blood pressure was markedly elevated in both the systemic and kidney-specific transgenic mice. Acute administration of the selective ANG II AT-1 receptor antagonist losartan lowered blood pressure in the systemic model but not in the kidney-specific model. These results provide evidence for the potential importance of the intrarenal RAS in blood pressure regulation by showing that expression of AGT specifically in the kidney leads to chronic hypertension independently of the endocrine RAS.

Topics: Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Gene Targeting; Humans; Hypertension; Kidney; Losartan; Mice; Mice, Transgenic; Organ Specificity; Promoter Regions, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; RNA, Messenger

Genetic factors play very important role in the pathogenesis of essential hypertension. Angiotensinogen gene is one of the candidate genes in the research concerning genetic background of elevated blood pressure. The aim of this work was to assess an association of M235T polymorphism in human angiotensinogen gene with essential hypertension in Polish population. 250 patients with essential hypertension and 150 normotensives were involved in the study. M235T polymorphism was detected using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Polymorphic allele and genotypes frequencies did not differ between hypertensive and normotensive groups. However T allele and TT genotype frequency among hypertensive men was higher than in normotensive men. The difference is statistically significant. T allele and TT genotype occurred more frequently in hypertensives with positive family history of essential hypertension. The difference between hypertensive men with positive family history and normotensive men was even more significant. This results are similar to those already published by other authors concerning Caucasian populations and indicate that angiotensinogen gene is involved in the determination of at least some cases of essential hypertension.

Topics: Alleles; Angiotensinogen; Female; Gene Expression; Humans; Hypertension; Male; Middle Aged; Poland; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Population Surveillance

The renin-angiotensin system plays a major role in regulating blood pressure and maintaining electrolyte and volume homeostasis. Previously, the angiotensinogen gene, which encodes the key substrate for renin within this system, has been reported linked to and associated with essential hypertension in White Europeans, African-Caribbeans, and Japanese. Therefore, we investigated whether the angiotensinogen gene might be similarly implicated in the pathogenesis of essential hypertension in Chinese by carrying out linkage analysis in 310 hypertensive sibling pairs. Genotypes for two diallelic DNA polymorphisms observed at amino acid residues 174 (T174M) and 235 (M235T) within the coding sequence and for two highly informative dinucleotide (GT)-repeat sequences (one in the 3' flanking region, and one at a distance of 6.1 cM from the gene) were determined. Affected sibpair analysis conducted according to three different algorithms (S.A.G.E./SIBPAL, MAPMAKER/ SIBS, and APM methods) revealed no evidence for linkage of the angiotensinogen gene to hypertension. Our data indicate that molecular variants of this gene do not appear to contribute materially to the pathogenesis of primary hypertension among Chinese (a notion supported by concomitant, direct estimates of power), and that the disease relevance of this gene may vary therefore depending on ethnicity.

Topics: Alleles; Angiotensinogen; Asian People; Female; Genetic Linkage; Genetic Markers; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

Different family and case-control studies support genetic linkage and association at the human angiotensinogen (AGT) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3'-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.

Topics: Adult; Alleles; Angiotensinogen; Dinucleotide Repeats; Europe; Family; Female; Gene Frequency; Genetic Linkage; Humans; Hypertension; Male; Microsatellite Repeats; Middle Aged; Polymorphism, Genetic

The renin-angiotensin system (RAS) is involved in the pathogenesis of essential hypertension. In the present study we examined the genotype frequencies of the insertion/deletion polymorphisms of the ACE gene and the M235T polymorphism of the Angiotensinogen (Agt) gene in patients with essential hypertension in comparison with normotensive subjects. In hypertensive patients functional effects of blood pressure response to ACE inhibition were investigated. A total of 121 patients with essential hypertension (group 1) and 125 normotensive control subjects (group 2) were included in this study. All patients were genotyped by polymerase chain reactions (PCR) for the insertion/deletion (I/D) polymorphism of the ACE gene and the M235T polymorphism of the Agt gene. To analyze possible functional impacts on blood pressure regulation 50 mg of captopril was administered to hypertensive patients. No significant association of essential hypertension with polymorphisms of the Agt and ACE gene was found. The ACE serum levels in patients with the DD-genotype of the ACE I/D polymorphism were higher than in patients with the II-genotype (P < .01). In patients with the ID-genotype the ACE serum levels were in-between. A captopril test was performed in hypertensive patients. The patients were further divided into subgroups according to the diastolic and systolic blood pressure response. Group 1a consisted of patients with a diastolic blood pressure drop of > 5 mm Hg and group 1b with < or =5 mm Hg. Group 1c consisted of patients with a systolic blood pressure drop of > 10 mm Hg and group 1d with < or =10 mm Hg. Twice as many patients with the DD genotype of the ACE gene were found in group 1a compared to group 1b (chi(2) = 5.673; P = .017). No association of systolic blood pressure change to the investigated polymorphisms was found. Our results do not support the hypothesis that the investigated polymorphisms contribute to essential hypertension. Furthermore, no major impact of these polymorphisms on blood pressure response to captopril were detected. We conclude that the investigated genotypes have no influence on blood pressure level and homeostasis.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To investigate a possible involvement of polymorphisms of the renin-angiotensin system in predisposition to moderate and severe hypertension and their relationship to parental histories of myocardial infarction and stroke.. Hypertensive cases (453 men, 326 women) were patients followed up by general practitioners for established hypertension. Inclusion criteria were an age of onset of hypertension < or = 60 years and a diastolic blood pressure > or = 105 mmHg without antihypertensive medication or > or = 100 mmHg under treatment. Normotensive controls were selected from population-based samples (362 men) and during a preventative medicine visit (170 women). Polymorphisms of the angiotensinogen gene (AGT M235T and T174M), the angiotensin I converting enzyme gene (ACE I/D), and the angiotensin II type 1 receptor gene (AGT1R A1166C) were investigated.. The AGTT235 allele prevalence was higher among male hypertensive cases than it was among controls (0.46 versus 0.40, P = 0.01) and a similar trend was observed with female cases whose hypertension had been diagnosed before they were aged 45 years (0.44 versus 0.38, P = 0.20). The AGT1R C1166 allele prevalence was higher among female hypertensives than it was among controls (0.30 versus 0.23, P = 0.03) but no such difference was observed for men. The AGT T174M and ACE I/D polymorphisms were not associated with hypertension. Hypertensive patients reporting a parental history of myocardial infarction before age 60 years had a higher prevalence of the ACE D allele than did those without such a parental history (0.68 versus 0.56, P = 0.01). The ACE D allele prevalence was also greater among patients reporting a parental history of stroke incidence before age 65 years (0.66 versus 0.57, P = 0.05).. These results support the hypothesis that the AGT gene plays a role in predisposition to hypertension and that the ACE gene plays a role in predisposition to acute ischemic events.

Topics: Adult; Alleles; Angiotensinogen; Cerebrovascular Disorders; Female; France; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Parents; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors

Transgenic animals are new and important models for the study of candidate genes in hypertension research as well as in other fields of medicine. For detailed genetic characterization of the transgenic animals, and to account for the symptoms arising from the insertion of transgenes in the genome, it is essential to identify these insertion sites. In this study, the insertion sites of the transgenes of candidate genes for hypertension were identified by fluorescence in situ hybridization (FISH) after G-banding of the chromosomes in transgenic rats and mice. This technique combines high resolution G-banding and fluorescence in situ hybridization for the mapping of four different candidate genes in six different transgenic rats as well as three different mouse transgenic lines. The presented results will help to draw conclusions about the influence of the respective integration site on transgene expression.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Chromosome Banding; Chromosome Mapping; Disease Models, Animal; Endothelin-2; Humans; Hypertension; In Situ Hybridization, Fluorescence; Mice; Mice, Transgenic; Rats; Rats, Sprague-Dawley; Renin

The aim of the study was to assess the effects of chronic angiotensin I receptor blockade on blood pressure, the renin-angiotensin system in plasma and kidney and the extent of renal damage in spontaneously hypertensive rats of the stroke prone strain (SHRsp). Four months old male SHRsp rats were orally treated with a high (10 mg/kg b.w. per day) or a low dose (1 mg/kg b.w. per day) of the AT1 receptor antagonist Telmisartan and compared to Losartan- (20 mg/kg b.w. per day), Captopril-treated (50 mg/kg b.w. per day) or untreated control groups for 38 days. Despite a similar extent of blood pressure reduction in all groups (except low dose Telmisartan), high dose Telmisartan but not Losartan or Captopril significantly reduced left ventricular weight by 24% compared to controls (p<0.05). Renal damage as assessed by urinary albumin or glomerulosclerosis index was significantly reduced in all treatment groups (p<0.02). Plasma renin concentration was significantly elevated (p<0.02) and plasma angiotensinogen significantly lowered (p<0.05) in all pharmacologically treated group compared to controls. In the kidney, renin-mRNA as well as AT1 receptor gene expression were elevated in all treatment groups, but no significant changes were found for renal angiotensinogen-mRNA. Chronic oral treatment of genetically hypertensive rats by the AT1 receptor antagonist Telmisartan reveals a blood pressure lowering and reno-protective effect of this drug comparable to other AT1 receptor antagonists or converting enzyme inhibitors, and demonstrates a marked reduction of cardiac hypertrophy by Telmisartan in this model.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Captopril; Cerebrovascular Disorders; Gene Expression; Hypertension; Kidney; Losartan; Male; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Telmisartan

This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women.

Topics: Adult; Angiotensinogen; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Genotype; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Odds Ratio; Point Mutation; Polymorphism, Genetic; Sex Factors

Hypertensive cardiac hypertrophy is associated with the accumulation of collagen in the myocardial interstitium. Previous studies have demonstrated that this myocardial fibrosis accounts for impaired myocardial stiffness and ventricular dysfunction. Although cardiac fibroblasts are responsible for the synthesis of fibrillar collagen, the factors that regulate collagen synthesis in cardiac fibroblasts are not fully understood. We investigated the effects of angiotensin II on cardiac collagen synthesis in cardiac fibroblasts. Cardiac fibroblasts of 10 week old spontaneously hypertensive rats and age-matched Wistar-Kyoto rats were prepared and maintained in culture medium supplemented with 10% fetal calf serum. The expression of mRNA of the renin-angiotensin system (renin, angiotensinogen, angiotensin converting enzyme) was determined by using a ribonuclease protection assay. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6 fold greater than that in the cell of Wistar-Kyoto rats. Angiotensin II stimulated collagen synthesis in cardiac fibroblasts in a dose-dependent manner. The responsiveness of collagen production to angiotensin II was significantly enhanced in cardiac fibroblasts from spontaneously hypertensive rats (100 nM angiotensin II resulted in 185 +/- 18% increase above basal levels, 185 +/- 18 versus 128 +/- 19% in Wistar-Kyoto rats p < 0.01). This effect was receptor-specific, because it was blocked by the competitive inhibitor saralasin and MK 954. These results indicate that collagen production was enhanced in cardiac fibroblasts from spontaneously hypertensive rats, that angiotensin II had a stimulatory effect on collagen synthesis in cardiac fibroblasts, and that cardiac fibroblasts from spontaneously hypertensive rats were hyper-responsive to stimulation by angiotensin II. Level of angiotensin and renin mRNA expressed in ventricles, and angiotensinogen mRNA expressed in fibroblasts from SHR were higher than those from WKY. These findings suggest that the cardiac renin-angiotensin system may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Collagen; Hypertension; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger

In the renin-angiotensin system, renin is known to cleave angiotensinogen to generate angiotensin I, which is the precursor of angiotensin II. Angiotensin II is a vasoactive peptide that plays an important role in blood pressure. On the other hand, the liver is the major organ responsible for the production of angiotensinogen in spontaneously hypertensive rats (SHR). To test the hypothesis that a reduction of angiotensinogen mRNA in the liver by antisense oligodeoxynucleotides (ODNs) may affect both plasma angiotensinogen and angiotensin II levels, as well as blood pressure, we intravenously injected antisense ODNs against rat angiotensinogen coupled to asialoglycoprotein carrier molecules, which serve as an important regulator of liver gene expression, into SHR via the tail vein. The SHR used in the present study were studied at 20 weeks of age and were fed a standard diet throughout the experiment. Plasma angiotensinogen, angiotensin II concentrations, and blood pressure all decreased from the next day until up to 5 days after the injection of antisense ODNs. These concentrations thereafter returned to baseline by 7 days after injection. A reduction in the level of hepatic angiotensinogen mRNA was also observed from the day after injection until 5 days after injection with antisense ODNs. However, in the SHR injected with sense ODNs, plasma angiotensinogen, angiotensin II concentrations, and blood pressure, as well as hepatic angiotensinogen mRNA, did not significantly change throughout the experimental period. Although the exact role of angiotensinogen in hypertension still remains to be clarified, these findings showed that intravenous injection with antisense ODNs against angiotensinogen coupled to asialoglycoprotein carrier molecules targeted to the liver could thus inhibit plasma angiotensinogen levels and, as a result, induce a decrease in blood pressure in SHR.

Topics: Angiotensinogen; Animals; Blood Pressure; Gene Expression Regulation; Hypertension; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; RNA, Messenger

The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance.. Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components-based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I-converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme (ACE) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% (P=0.04), and 16% (P=0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [P=0.005], and 32% [P<0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [P=0.03], 38% for DBP [P=0.04], and 53% for MAP [P<0.005]) but not in females.. Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.

Topics: Adolescent; Angiotensinogen; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Diastole; Disease Susceptibility; Genetic Linkage; Genetic Variation; Genotype; Humans; Hypertension; Male; Microsatellite Repeats; Minnesota; Nuclear Family; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Risk Factors; Sampling Studies; Sex Characteristics; Systole; White People

To prove whether the interaction between insertion/deletion (I/D) angiotensin I converting enzyme (ACE) and M235T angiotensinogen (AGT) gene polymorphic alleles could contribute to causing essential hypertension, we examined subjects from the Czech Republic (365 Caucasians total; 202 normotensives and 163 hypertensives). Subjects were genotyped for insertion/deletion polymorphism of ACE (I/D ACE, intron 16) and for M235T polymorphism of angiotensinogen gene (AGT, exon 2) by means of the polymerase chain reaction (PCR) method. The case-control approach was used. Fisher's exact test followed by Holmes's test to overcome the problem of multiple comparisons were used for the statistical analysis of data. No association of single gene allelic variants with essential hypertension was found in our population. Having compared only double homozygote combinations, the association of the DDMM genotype with essential hypertension was proven (P = 0.0081). To the contrary, IITT (P = 0.0086) was found more frequently in normotensive subjects. We conclude that the interaction of the I/D ACE and M235T AGT polymorphic alleles can contribute to essential hypertension, despite the absence of single gene associations with the condition.

Topics: Adult; Alleles; Angiotensinogen; Body Mass Index; Case-Control Studies; Female; Forecasting; Genes; Genetic Variation; Genotype; Homozygote; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Probability; Reference Values

The molecular variants M235T and T174M of the angiotensinogen gene have been linked to essential hypertension in some populations, but there are discrepancies about this association in other studies. We studied 75 patients with essential hypertension (BP > 160/100 mm Hg) from our outpatient clinic, aged 55+/-1 years, 30 men, systolic BP 182+/-2.5, diastolic BP 109+/-1 mm Hg (mean +/- SEM), and a family history of the disease. Target organ damage was evaluated by measuring urinary albumin excretion rate, left ventricular hypertrophy, and fundoscopy. As a control group, 75 healthy subjects with BP < 130/85 mm Hg and with no family history of cardiovascular disease were selected. M235T and T174M angiotensinogen genotypes were determined by PCR and subsequent digestion of the products with SfaNI and NcoI, respectively. The frequency (q) of genotypes of the variant M235T in the patients with essential hypertension was MM 0.31, MT 0.41, and TT 0.28, not significantly different (P = .93) from that of the controls (MM 0.28, MT 0.44, and TT 0.28). For the variant T174M, the genotype frequencies in hypertensives were TT 0.83, TM 0.15, and MM 0.02, which was not significantly different (P = .89) from that of the controls (TT 0.86, TM 0.12, and MM 0.02). Similarly, there was no evidence for association between angiotensinogen genotypes and hypertension in subjects aged < or = 40 years old (n = 24) or with severe (stage III) hypertension (n = 31). Within the group of patients with essential hypertension, there were no differences in genotype distribution between patients with and without retinopathy (n = 31), left ventricular hypertrophy (n = 37), or microalbuminuria (n = 14). This study shows that M235T and T174M variants are not associated either with essential hypertension or with target organ damage in a Spanish sample.

Topics: Adult; Aged; Albuminuria; Alleles; Angiotensinogen; Echocardiography; Female; Gene Frequency; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Polymorphism, Genetic

Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findings, it was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hypertrophy and renal glomerular sclerosis by inhibiting RAS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Cardiomegaly; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Kidney; Lisinopril; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Renin; Renin-Angiotensin System

We previously reported significant associations between variation in the AGT gene at codon 235 and both systolic pressure and hypertension in Canadian Oji-Cree. Recently, Inoue et al suggested that the AGT T235 variant was not causative, but was rather in linkage disequilibrium with a variant in the AGT promoter, namely -6A, that was associated with increased in vitro expression of angiotensinogen and was thus a strong candidate to be the functional basis of the previously observed associations. We genotyped 518 adult Oji-Cree for the AGT promoter polymorphism and tested for its association with blood pressure and hypertension. We found that the frequency of the -6A variant was 0.85 in the Oji-Cree, which is much higher than the frequency observed in other human samples. We also found strong linkage disequilibrium between the AGT -6A and T235 variants. However, genetic variation of the AGT promoter was only marginally associated with variation in systolic pressure, with a trend to significantly higher systolic pressure seen in AGT -6A/A homozygotes than in subjects with other genotypes. In addition, genetic variation of the AGT promoter tended to be associated with a diagnosis of hypertension. Despite the very high prevalence of -6A, our native sample was essentially normotensive. Our findings are consistent with a marginally deleterious effect of the AGT -6A allele on blood pressure, but linkage disequilibrium with another causative variant cannot be ruled out in this sample of aboriginal Canadians.

Topics: Adult; Angiotensinogen; Base Sequence; Blood Pressure; Canada; DNA Primers; Female; Gene Frequency; Genetic Variation; Humans; Hypertension; Indians, North American; Linkage Disequilibrium; Male; Middle Aged; Promoter Regions, Genetic

Rats exposed chronically to mild cold (5 degrees C/41 degrees F) develop hypertension and cardiac hypertrophy. This provides a unique model of hypertension that is environmentally induced. The blood renin-angiotensin system (RAS) has been shown to play a role in both initiating and maintaining the high blood pressure (BP) in cold-induced hypertension. The mechanism also appears to involve both the tissue and brain RAS because there is increased mRNA for angiotensinogen (AGT) and angiotensin type 1 (AT1) receptors in brain and peripheral tissues, an increased spontaneous drinking response, and an increased dipsogenic response to acute administration of angiotensin II (Ang II) in cold-treated rats. Antisense oligodeoxynucleotides (AS-ODN), targeted to the RAS, have been shown to reduce BP in spontaneously hypertensive rats. Therefore, we injected AS-ODN in rats with cold-induced hypertension to test whether antisense inhibition was effective in reducing this nongenetic nonsurgical hypertension. Sprague-Dawley rats were made hypertensive by cold exposure and injected intracerebroventricularly with AS-ODN to AGT mRNA (n=6) or AT1 receptor mRNA (n=6). Systolic BP was recorded by tail cuff 24 hours later for 2 or 7 days, respectively. Systolic BP decreased significantly in response to AGT-AS-ODN (40+/-6 mm Hg, P<0.01) within 1 day after injection and to AT1 receptor-AS-ODN (P<0.05) for 3 days after injection. The maximum decrease was 41+/-10 mm Hg. Systolic BP then gradually increased to the preinjection level. The spontaneous drinking response to cold treatment also decreased significantly (P<0.05) after AGT-AS-ODN or AT1 receptor-AS-ODN intracerebroventricular injection. Intracardiac injection of AT1-AS-ODN (n=6) reduced systolic BP by 36+/-8 mm Hg (P<0.05) and decreased AT1 receptor as measured by autoradiography in aorta, adrenal glands, and kidneys 24 hours after injection. These data show that AS-ODN reduces BP in cold-induced hypertension and that the hypertension involves both peripheral tissues and central RAS in addition to blood-borne RAS mechanisms.

Topics: Adrenal Glands; Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Antisense Elements (Genetics); Aorta; Autoradiography; Blood; Blood Pressure; Brain; Cold Temperature; Drinking; Hypertension; Kidney; Male; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Time Factors

The angiotensinogen gene has recently been linked to essential hypertension. A variant within this gene, encoding threonine rather than methionine at amino acid position 235, was associated with essential hypertension. However, results of new studies have not confirmed this association, suggesting that ethnic differences may explain the different results.. To evaluate whether the T235 variant is associated with a higher incidence of essential hypertension among Hispanics (a group that has scarcely been evaluated) and to determine whether T235 is associated with variations in the plasma renin activity or the serum aldosterone level.. We studied 64 patients with essential hypertension and 62 normotensives, matched for age and sex. We obtained samples for determinations of plasma renin activity, serum aldosterone level and genome DNA from all subjects. The genomic DNA was amplified using the polymerase chain reaction technique and digested by the restriction enzyme streptococcus faecalis (Sfa NI) which cuts M235 only, not T235.. The patients with essential hypertension had a higher prevalence of the risk variant T235 (alleles 77/128 = 60.2%) than did the normotensive controls (alleles 65/124 = 52.4%), but the difference was not statistically significant (chi2=1.53, P=0.22). The plasma renin activity levels in hypertensives were not statistically different for homozygous T235, heterozygous and homozygous M235 (1.0 +/- 0.96, 2.0 +/- 2.25 and 1.55 +/- 1.49 ng/ml per h, respectively, P=0.5 1). However, when we considered those hypertensives with low plasma renin activity levels (< 1 ng/ml per h), we found a high prevalence (72.7%) of subjects homozygous for the T235 variant. We found no association between the T235 variant and the serum aldosterone levels in hypertensive and normotensive subjects.. We demonstrated that there is a high prevalence of T235 variant in our Hispanic population. The slight difference between prevalences of T235 variant among hypertensive and normotensive subjects that we found was not statistically significant and did not permit us to establish an association between T235 variant and essential hypertension. We believe that only studying a larger cohort of subjects could show whether there is a quantitative effect of the T allele on plasma renin activity levels.

Topics: Aldosterone; Angiotensinogen; Blood Pressure; Chile; DNA; DNA Primers; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Prevalence; Renin

In our experiments, we evaluated the possible effect of M235T molecular variant of the angiotensinogen gene on the response to a physical workload. A group of volunteers was composed of healthy male subjects, approximately of the same weight and height, same age and not actively trained. None of these subjects was under any medication. Blood sampling was carried out via an indwelling catheter. Besides blood pressure and heart rate, angiotensin I, angiotensin II, epinephrine and norepinephrine concentrations were measured in the blood. Our results suggest that only the response of diastolic blood pressure during submaximal exercise corresponded to the presence of M235T molecular variant. In all other parameters we found no significant correlation of the response with the M235T molecular variant.

Topics: Adult; Angiotensinogen; Angiotensins; Blood Pressure; Cardiovascular Physiological Phenomena; Endocrine System; Epinephrine; Exercise; Genetic Markers; Heart Rate; Humans; Hypertension; Male; Norepinephrine; Polymerase Chain Reaction; Polymorphism, Genetic

Variants of renin-angiotensin system genes are shown to be associated with cardiovascular pathology. The association between renin-angiotensin system genes and left ventricular mass was investigated in a population-based case-control study.. The association between echocardiographic left ventricular mass and both insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the methionine-threonine variant at position 235 of the angiotensinogen gene was studied in a random cohort of 430 hypertensive and 426 control subjects. No differences in the adjusted left ventricular mass values between the different genotypes were seen among either the hypertensive or the control subjects, whether men or women, or in the subgroups of normotensive or physically active subjects. Gene variation had no statistically significant synergistic effect on left ventricular mass values. In control women, the deletion allele of the angiotensin-converting enzyme gene was associated with an increased risk of left ventricular hypertrophy. However, this finding was based on a small number of women with left ventricular hypertrophy and should be interpreted with caution.. Variations in renin-angiotensin system genes had no major effect on left ventricular mass in this middle-aged population-based cohort of hypertensives and control subjects.

Topics: Adult; Alleles; Angiotensinogen; Cardiac Volume; Case-Control Studies; Chromosome Deletion; Cohort Studies; Echocardiography; Female; Genetic Variation; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors

1. Early studies suggest that hypertension in Dahl salt-sensitive (S) rats is related to an uncommon humoral factor that may be released from the kidney. 2. To investigate whether the kidney releases a hypertensinogenic factor for developing salt-induced hypertension in S rats, we examined a pressor effect, or vascular contractive activity of a kidney extract from S rats using a conscious recipient rat or an isolated aortic ring. 3. Donor S and Dahl salt-resistant (R) rats were fed a 0.4 or 8% NaCl diet for 4 weeks and were then used to provide four kinds of kidney extracts (S-0.4%, S-8%, R-0.4%, R-8%). The systolic arterial pressure (SAP) was significantly increased in donor S rats fed an 8% NaCl diet compared with other donor rat groups. 4. All four types of kidney extract increased mean arterial pressure (MAP) in a recipient rat fed a 0.4% NaCl diet. However, the increase in MAP observed following infusion of the S-8% extract was the least of all groups. An angiotensin AT1 receptor antagonist, CV-11974, abolished any pressor effect of all kidney extracts. In an in vitro experiment, all four types of kidney extract evoked contractile responses in aortic rings, but elicited no significant difference in aortic ring contractile force. 5. These results suggest that the kidney of S rats may not release an active hypertensinogenic factor that would cause salt-induced hypertension.

Topics: Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Aorta; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Hypertension; In Vitro Techniques; Kidney; Muscle Contraction; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium Chloride; Tetrazoles; Tissue Extracts

To compare the distributions of the genotypes and alleles of the M235T polymorphism of the angiotensinogen gene for hypertensive patients and normotensive controls.. A study of association of genetic polymorphisms.. An outpatient clinic run by a university department handling referrals from primary care.. Two hundred and four subjects, 103 normal controls and 101 patients with newly diagnosed or documented hypertension.. Genomic DNA was extracted from peripheral blood leucocytes, amplified by polymerase chain reaction and digested with the restriction enzyme Tth 111 I. Methionine (M) and threonine (T) alleles were identified after electrophoresis.. Prevalences of angiotensinogen genotypes and alleles for hypertensive patients and controls.. MM, TM and TT genotypes occurred in 3, 24 and 73% of controls and 1, 22 and 77% of hypertensive patients, respectively. The prevalences of the M and T alleles were 0.15 and 0.85 among controls and 0.12 and 0.88 among hypertensive patients. The prevalences of the angiotensinogen genotypes and alleles for controls and hypertensive patients did not differ significantly.. Our findings differed from previous reports and suggested that this polymorphism is not associated with hypertension in this population.

Topics: Adult; Aged; Alleles; Angiotensinogen; Case-Control Studies; China; DNA; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic

To date, the human angiotensinogen (AGT) gene and some of its variants represent the best examples of genetic influences that are involved in the determination of essential hypertension (EH) and associated cardiovascular diseases (CVDs). To assess the value of genotyping AGT in a genetically homogeneous population, we carried out a retrospective, case control study of variants M235T and T174M for putative correlations with CVDs among nationals from the United Arab Emirates (Emirati)--an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 229 Emirati (119 males and 110 females), comprising groups of controls and patients with clinical diagnoses of EH, left ventricular hypertrophy (LVH), ischaemic heart disease (IHD) and myocardial infarction (MI). M235T and T174M alleles were determined via assays based on the polymerase chain reaction. T174M showed no correlation with any of the four clinical entities included in this study. T235 alleles, however, occurred more frequently in the EH group and less frequently in the group of MI survivors. We also found that T235 allele frequencies decreased with age, indicating that in the Emirati population, T235 alleles are associated with a reduced life span and that this effect could occur through independent mechanisms underlying genetic susceptibilities to both EH and MI.

Topics: Adult; Aged; Alleles; Amino Acid Substitution; Angiotensinogen; Body Mass Index; Case-Control Studies; Cholesterol; DNA Mutational Analysis; Female; Genes; Genetic Testing; Genotype; Humans; Hypertension; Male; Middle Aged; Mutation; Myocardial Infarction; Myocardial Ischemia; Phenotype; Pilot Projects; Retrospective Studies; Statistics as Topic; United Arab Emirates; Ventricular Dysfunction, Left

In this study we wanted to evaluate the relationship between the ob gene product leptin and blood pressure, as well as plasma renin activity and plasma aldosterone levels. We studied 139 subjects with a mean+/-SD age of 50 +/-14 years and a body mass index of 26.5+/-5.3 kg/m2; 110 subjects had essential hypertension and 29 were healthy nonhypertensive controls. Blood pressure was measured in resting conditions in the morning and blood was drawn for the determination of the plasma renin activity, aldosterone, and leptin levels. The mean blood pressure of the population was 155/97 mm Hg. The relationship between these parameters was studied by univariate regression analysis according to gender and, whenever indicated, adjusted for age and body mass. The mean+/-SEM plasma leptin level in the whole population was 9.5+/-0.6 ng/mL (range, 1.1-43.3). Subjects with stage I hypertension had significantly higher plasma leptin levels than normotensive subjects. Systolic blood pressure correlated with the plasma leptin levels and the leptin levels adjusted for body weight in women (r = 0.422, P < .01) and nonhypertensive men (r = 0.644, P = .03) only. Plasma renin activity (r = 0.329, P = .03) and aldosterone levels (r = 0.342, P = .026) correlated with the leptin concentration. A significant relationship between the peripheral expression of the ob gene product leptin and systolic blood pressure was found in women and nonhypertensive men. In view of the multiple functions of leptin a causal relationship is postulated and potential mechanisms may involve modulatory effects of leptin on neuropeptide Y, angiotensinogen gene expression, the modulation of the autonomous nervous system, or effects on the pituitary adrenal axis. Direct relationships between both plasma renin activity and aldosterone levels and leptin support the potential importance of the relationship between leptin and blood pressure. Our observation may be of future importance for the understanding of the link between the increase in blood pressure and increasing body weight.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Female; Humans; Hypertension; Leptin; Male; Middle Aged; Obesity; Proteins; Renin

The hypertensive double transgenic rat harboring both the human renin and human angiotensinogen genes (dTGR) offers a unique opportunity to study the human renin-angiotensin system in an experimental animal model. Since nothing is known about the control of sodium and water excretion in these rats, this study was performed to compare pressure-natriuresis relationships in hypertensive dTGR and normotensive control rats harboring only the human renin gene (hREN), in order to determine how the pressure-natriuresis relationship is reset in hypertensive dTGR. To differentiate between extrinsic and intrinsic renal mechanisms, experiments were performed with and without renal denervation, and with and without infusions of vasopressin, norepinephrine, 17-OH-corticosterone, and aldosterone. Human and rat angiotensinogen and renin mRNA expression were also determined. In hREN without controlled renal function, urine flow and sodium excretion increased from 13 to 169 microl/min per g kidney wet weight (kwt) and from 1 to 30 micromol/min per g kwt, respectively, as renal perfusion pressure was increased from 67 to 135 mmHg. Renal blood flow (RBF) and GFR ranged between 3 to 7 and 0.9 to 1.5 ml/min per g kwt. In dTGR, pressure-natriuresis-diuresis relationships were shifted approximately 40 mmHg rightward. RBF was lower in dTGR than in hREN; GFR was not different. In dTGR with neurohormonal factors controlled, RBF was decreased and pressure-natriuresis-diuresis curves were not different compared to dTGR curves without these interventions. By light microscopy, the kidneys of these 6-wk-old dTGR and hREN rats were normal and indistinguishable. Both human and rat renin and angiotensinogen mRNA were expressed in the kidneys of dTGR. The two renin mRNA were decreased in dTGR, indicating a physiologic downregulation of renin gene expression by high BP. It is concluded that the renal pressure-natriuresis mechanism is reset toward higher pressure levels in dTGR and participates in the maintenance of hypertension. The reduced excretory function in dTGR depends on hREN and human angiotensinogen gene expression and is intrinsic to the kidney as opposed to extrarenal regulators.

Topics: Aldosterone; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Diuresis; Humans; Hypertension; In Situ Hybridization; Inulin; Male; Metabolic Clearance Rate; Natriuresis; p-Aminohippuric Acid; Rats; Recombinant Fusion Proteins; Renin; Renin-Angiotensin System

The M235T polymorphism of human angiotensinogen is associated with essential and pregnancy-induced hypertension. A covalent complex is formed between angiotensinogen and the proform of the eosinophil major basic protein (proMBP) during pregnancy. The sequence of human angiotensinogen contains four cysteines. Their function was analyzed. Presence of free cysteines was demonstrated by their alkylation with iodo[14C]acetic acid. A disulfide bond between Cys18 and Cys138 using a fully N-deglycosylated mutant of human angiotensinogen was identified by tryptic digestion and mass spectrometry. We produced angiotensinogen. proMBP complex by co-transfection of COS-7 cells and by co-culturing transfected CHO-K1 cells. Experiments with 8 mutated recombinant angiotensinogen, in which one or more of the four cysteines were replaced by alanine, demonstrated that Cys232 is involved in complex formation and could interact with the M235T variant. The angiotensinogen.proMBP complex was isolated by molecular sieving. Hydrolysis of the complex by human renin was 7 times slower than hydrolysis of monomeric form, whatever the M235T genotype. The complex:monomeric angiotensinogen ratio was greater for Met235 (72%) than for Thr235 (58%) angiotensinogen. These data suggest a new pathophysiological explanation for the genetic association between M235T angiotensinogen polymorphism and pregnancy-induced hypertension.

Topics: Alkylation; Amino Acid Substitution; Angiotensinogen; Animals; Blood Proteins; Carbon Radioisotopes; CHO Cells; Cricetinae; Cysteine; Eosinophil Major Basic Protein; Female; Humans; Hypertension; Iodoacetates; Mutagenesis, Site-Directed; Peptide Fragments; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular; Protein Precursors; Proteoglycans; Recombinant Proteins; Transfection

We investigated the relation between atrial natriuretic factor (ANF) gene expression and the status of the renin-angiotensin system (RAS) in aortic tissue in rats made hypertensive by either aortic banding or by deoxycorticosterone acetate (DOCA)-salt administration. These experimental models of hypertension are known to have differences in terms of the status of RAS. ANF messenger RNA (mRNA) levels were measured in aortic tissue by using a newly developed quantitative competitive reverse transcription polymerase chain reaction (QC-RT-PCR) technique. Changes in the proportions of alpha1 and alpha2 isoforms of Na+K+-adenosine triphosphatase (ATPase) mRNA levels were used as indicators of aortic hypertrophy. Treatment with DOCA alone, salt alone, or DOCA-salt for 5 weeks increased aortic-weight/body-weight ratio and aortic angiotensinogen mRNA levels, but did not change alpha1 or alpha2 Na+K+-ATPase mRNA levels. Aortic ANF mRNA levels had a tendency to increase after treatment with DOCA, salt, or DOCA-salt, but this change did not reach statistical significance. Suprarenal aortic banding for 6 weeks or 12 weeks increased aortic-weight/body-weight ratio (12 weeks), decreased alpha2 Na+K+-ATPase and angiotensinogen mRNA levels, but did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Treatment with ramipril, an angiotensin-converting enzyme (ACE) inhibitor was carried out for 6 weeks just after aortic banding (prevention experiment) or after 6 weeks in rats that were banded for the previous 6 weeks (regression experiment). High-dose ramipril (1 mg/kg)--a treatment known to inhibit both tissue and circulating RAS--normalized aortic-weight/body-weight ratio, and also normalized alpha2 Na+K+-ATPase mRNA levels. Aortic angiotensinogen mRNA levels of banded rats treated with high-dose ramipril was higher than those of the normal control, sham operated, and banded rats. Treatment with high-dose ramipril did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Low-dose ramipril (10 microg/kg)--a treatment that selectively inhibits tissue RAS--normalized aortic-weight/body-weight ratio but did not normalize alpha2 Na+K+-ATPase mRNA levels (regression experiment) or angiotensinogen mRNA levels (prevention experiment) and did not change either alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. The results suggest that, in contrast to previous findings in heart and kidney, the regulation of ANF mRNA levels in aortic tissue is largely independent

Topics: Angiotensinogen; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Gene Expression; Gene Expression Regulation; Hypertension; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium-Potassium-Exchanging ATPase

To evaluate the relation of tissue-localized angiotensin II (Ang II) concentration with cardiac hypertrophy and glomerulosclerosis in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes.. Thirty THM aged 12 weeks were distributed equally to a lisinopril dosage group, a hydralazine dosage group, and an untreated group. Ten age-matched C57BL/6 mice were used as normal controls. Administration was performed for 8 weeks from 12 weeks of age. All mice were euthanized at 20 week of age, and the heart-to-body weight ratio, the renal glomerulosclerosis score, tissue Ang II concentration and tissue catecholamine concentration were measured.. In the untreated group, a significant increase in every examination item was found as compared with that in C57BL/6 mice. In the lisinopril group, the observed value of every item was significantly lower than that in the untreated group. In the hydralazine group, tissue Ang II and catecholamine concentrations and the heart-to-body weight ratio were not different from those in the untreated group. Although the glomerulosclerosis score in the hydralazine group was significantly less than that in the untreated group, this was significantly higher than that in the lisinopril group.. Tissue Ang II concentration is more important than hypertension in causing cardiac hypertrophy, and both tissue Ang II level and hypertension are important in causing glomerulosclerosis in THM.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Catecholamines; Humans; Hydralazine; Hypertension; Kidney Diseases; Lisinopril; Mice; Mice, Inbred C57BL; Mice, Transgenic; Renin

Oral estrogen replacement therapy (ERT) is known to stimulate the synthesis of angiotensinogen. The effects of such therapy on renin, ACE, and aldosterone are less clear. This seems noteworthy, however, since further activation of the system could be disadvantageous to postmenopausal women who replace estrogen in the context of heart failure, coronary artery disease, or hypertension.. Estrogen status and components of the renin-angiotensin system were examined in a population-based sample of postmenopausal women and age-matched men. Renin was quantified immunoradiometrically, ie, independent of substrate abundance; aldosterone, angiotensinogen, and ACE activity were determined by standard methods. Renin levels were lower in women with ERT (n = 107; 12.0 +/- 0.7 mU/L) compared with women without ERT (n = 223; 16.6 +/- 0.9 mU/L; P = .001) or men (n = 342, 20.5 +/- 1.5 mU/L, P < .0001). In contrast, angiotensinogen was higher in women with ERT (1.36 +/- 0.08 mg/L) compared with women without ERT (1.03 +/- 0.02 mg/L; P < .0001) or compared with men (0.97 +/- 0.01 mg/L; P < .0001). Renin suppression was seen with either oral or transdermal estrogen replacement (-30% and -31%, respectively; both P < .001). In contrast, the increase of angiotensinogen was limited to women taking oral estrogens (+58%, P < .001). Multivariate analysis revealed that these estrogen effects were independent of age, body mass index, blood pressure, and/or antihypertensive medication. Finally, only marginal differences between groups were observed for serum ACE activity and aldosterone.. Aside from a well-documented induction of angiotensinogen, ERT is related to a substantial suppression of renin, a phenomenon that might have received little attention because of widely used indirect measurements of the hormone.

Topics: Aged; Aldosterone; Analysis of Variance; Angiotensinogen; Estradiol; Estriol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Hypertension; Male; Middle Aged; Postmenopause; Renin; Renin-Angiotensin System

In studies conducted in several different populations, the M235T substitution in the angiotensinogen (AGT) locus has been associated with hypertension.. A case-control study was initiated in an attempt to replicate this finding. Persons with hypertension, age- and sex-matched normotensive controls, and randomly sampled individuals were probands from the Family Heart Study of the National Heart, Lung, and Blood Institute. Subjects were recruited from the Atherosclerosis Risk in Communities study (ARIC) in North Carolina and Minneapolis, MN, and from the Framingham Heart Study in Massachusetts. Genotypes were determined for the M235T substitution in the AGT locus and for the insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) locus. Simple association tests as well as logistic regression analyses were performed.. The association of AGT-T235 with hypertension was replicated in the Framingham sample (odds ratio, 1.60; 95% confidence interval, 1.11-2.30), but not in the ARIC white or black subjects. However, logistic regression analysis suggested a significant association of AGT with hypertension in both the ARIC white and Framingham samples when the effects of body mass index, triglycerides, and the presence of significant coronary heart disease were controlled. These analyses further suggested that, in the ARIC data, the relationship with the AGT locus is stronger in women than men and that there may be interaction (epistasis) between homozygotes for T235 and ACE-DD in the Framingham data. While the small sample size precluded logistic regression analysis, the frequency of the T235 allele in the black random sample was much higher than in the comparable white sample.. These results are compatible with the presence of a genetic risk factor for hypertension in or near the angiotensinogen locus.

Topics: Angiotensinogen; Black People; Body Mass Index; Case-Control Studies; Coronary Disease; Female; Genotype; Humans; Hypertension; Logistic Models; Male; Massachusetts; Middle Aged; Minnesota; North Carolina; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; Sex Factors; Triglycerides; White People

Variants of the angiotensinogen gene may increase the risk of developing arterial hypertension, but their effect on the use of antihypertensive medication in the general population remains unclear. Thus, we determined T174M and M235T allele status and angiotensinogen plasma levels in a cross-sectional sample of 634 middle-aged subjects (48.4% men) from the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg cohort study. We found no association between T174M allele status and angiotensinogen levels, blood pressure, or use of antihypertensive drugs. In contrast, multivariate analysis revealed that individuals who carried at least one copy of the T235 allele (n = 418) had higher systolic and diastolic pressures (P = .007) and .008, respectively) and were more likely to use an antihypertensive drug (1.6-fold risk, P = .04) than homozygotes for the M235 allele (n = 216). The likelihood of taking two or more antihypertensive medications was 2.1-fold higher in carriers of the T235 allele (P = .02). Overall, 22.5% of all antihypertensive drugs taken appeared to be attributable to the excess risk associated with this allele. These associations were replicated in two previous surveys carried out on the same individuals over 10 years. Furthermore, the T235 allele was related to higher angiotensinogen plasma levels [15.5 +/- 0.31 versus 16.5 +/- 0.15 (nmol/L)/L in homozygotes for the M235 and T235 alleles, respectively; P < .01], which were also related to systolic pressure (P = .03) and more intensive antihypertensive medication (P = .03). We conclude that the angiotensinogen T235 allele accounts for a substantial proportion of antihypertensive drug use in this middle-aged, population-based group of white subjects.

Topics: Aged; Alleles; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Cohort Studies; Female; Genetic Variation; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Time

Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes.

Topics: Adult; Aged; Alleles; Angiotensinogen; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Renin-Angiotensin System; Risk Factors; White People

The angiotensinogen gene is one of the very few related by linkage analysis to human hypertension, but the linkage has been consistently shown only among males. Moreover, polymorphisms in this gene predict an abnormal renal responsiveness to angiotensin II, a feature of non-modulation, but again, only among males. To pursue these related bridges between genetics and physiology, we evaluated the effects of sex on a second feature of non-modulation, the aldosterone response to infused angiotensin II during low sodium balance. We tested the resultant hypothesis-that non-modulation would be less frequent in women-by conducting identical protocols on 225 hypertensive inpatients (70 women, 155 men). Non-modulation was strikingly less frequent among women (26%; 95% confidence interval, 16% to 37%) than men (49%; 95% confidence interval, 40% to 57% (P = .001). We tested the hypothesis that sex steroids play a role by comparing young, premenopausal women (< 35 years) with women who were perimenopausal (45 to 55 years) and postmenopausal (> 55 years). Among the youngest women, the frequency of non-modulation was only 7%, significantly less than in young men (41%, P = .02). A steady increase in non-modulation frequency accompanied advancing age in women, reaching 47% in those older than 55 years, equal to the fraction of men affected. Age influenced non-modulation frequency in men far less. We conclude that a striking sex difference underlies the non-modulation phenotype and that female sex hormones may confer protection against a genotypic predisposition in women. This "override" of genotype, manifest by a very low frequency of non-modulation in young women, may participate in their known protection against cardiovascular disease.

Topics: Adolescent; Adult; Age Factors; Aged; Aldosterone; Angiotensin II; Angiotensinogen; Data Interpretation, Statistical; Female; Genotype; Humans; Hypertension; Infusions, Parenteral; Male; Menopause; Middle Aged; Phenotype; Postmenopause; Premenopause; Sex Factors

We examined the effect of chronic human renin infusion and human renin inhibition on blood pressure in a unique transgenic rat model. We infused incremental doses of human renin (1 to 500 ng/h) with minipumps for 10 days into rats harboring the human angiotensinogen gene [TGR (hAOGEN)1623]. We measured blood pressure and heart rate continuously by telemetry. We found that human renin at 5 ng/h was necessary to increase blood pressure, whereas 10 ng/h caused systolic blood pressure to increase to 215 +/- 13 mm Hg. Heart rate decreased initially but then increased by 100 beats per minute compared with basal values. Drinking behavior also increased. Doses as high as 500 ng/h did not increase blood pressure further. A linear relationship was found between the log of plasma renin activity and systolic blood pressure that increased in slope from days 2 to 9. Rat angiotensinogen levels were low and not influenced by human renin infusion. Human angiotensinogen levels remained stable until 500 ng/h human renin was infused, at which time they decreased by 50% at 9 days. Rat renin gene expression (RNase protection assay) was decreased by human renin infusion, whereas rat and human angiotensinogen gene expressions in liver and kidney as well as angiotensin-converting enzyme gene expression in kidney were not affected. The human renin inhibitor Ro 42-5892 was given by gavage repeatedly to rats receiving human renin at 40 ng/h. Ro 42-5892 lowered blood pressure promptly to basal values. High human renin hypertension in this model is dose dependent, features a steeper relationship between blood pressure and plasma renin activity over time, and is associated with tachycardia and increased drinking. We conclude that the human angiotensinogen transgenic rat offers new perspectives in the study of human renin-induced hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Gene Expression; Heart Rate; Humans; Hypertension; Imidazoles; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin; Telemetry; Time Factors

In earlier studies, we provided statistical evidence that individual differences in the angiotensinogen gene, the precursor of the vasoactive hormone angiotensin II, constitute inherited predispositions to essential hypertension in humans. We have now identified a common variant in the proximal promoter, the presence of an adenine, instead of a guanine, 6 bp upstream from the initiation site of transcription, in significant association with the disorder. Tests of promoter activity and DNA binding studies with nuclear proteins suggest that this nucleotide substitution affects the basal transcription rate of the gene. These observations provide some biological insight about the possible mechanism of a genetic predisposition to essential hypertension; they may also have important evolutionary implications.

Topics: Angiotensinogen; Binding, Competitive; Genotype; Humans; Hypertension; Promoter Regions, Genetic; Sodium; Transcription, Genetic; Tumor Cells, Cultured

The renin-angiotensin system (RAS) plays a crucial role in the regulation of fluid volume, thereby influencing blood pressure (BP). Obesity is an important risk factor for hypertension, however the physiologic basis for this relationship has not been clarified. In a population survey we examined the potential relationship between the RAS and obesity. Based on community sampling, 449 individuals were recruited from metropolitan Kingston, Jamaica. Serum angiotensin-converting enzyme (ACE) and circulating angiotensinogen levels were measured and the associated genes were typed for previously described polymorphisms. Obese individuals (body mass index > 31) had significantly higher serum ACE and angiotensinogen levels, this relationship persisted for ACE in multivariate analyses controlling for BP, hypertension status, age, and gender. The insertion/deletion polymorphism of the ACE gene was associated with variation in the levels of ACE, but inconsistently with body mass index. Variants of the angiotensinogen gene leading to amino acid substitutions at positions 174 and 235 did not influence levels either of angiotensinogen or obesity. These data suggest that obesity may alter the levels of ACE and angiotensinogen, and provide a potential pathway through which obesity leads to elevation of BP.

Topics: Adult; Angiotensinogen; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

We measured blood pressure and related clinical phenotypes in 497 adult native Canadians from an isolated community in Northern Ontario. We analyzed their DNA for genotypes of angiotensinogen. We found that the frequency of the T235 variant of the angiotensinogen gene was 0.89 in this sample. This variant was associated with a significantly increased systolic pressure but not diastolic pressure. We also found that sex and body mass were each highly significantly associated with variation in both systolic and diastolic pressures. We found a significant association between age and variation in systolic pressure but not diastolic pressure. We also found a highly significant association between plasma apolipoprotein B concentration and variation in diastolic pressure but not systolic pressure. The high frequency of the angiotensinogen T235 variant suggests that subjects in this young, essentially normotensive population might be predisposed to hypertension, which may become more apparent in the presence of secondary factors.

Topics: Adult; Age Factors; American Indian or Alaska Native; Angiotensinogen; Blood Pressure; Body Weight; Canada; Female; Humans; Hypertension; Male

A variant of the angiotensinogen gene (AGT) that encodes for threonine at codon 235 (T235) has been associated with a higher serum angiotensinogen concentration and with hypertension in white subjects. The frequency of T235 is about two times higher in blacks than whites, suggesting that AGT may contribute to the susceptibility to hypertension in blacks more than it does in whites. However, an association of T235 with angiotensinogen level or blood pressure has not been observed in blacks, possibly because the high prevalence of T235 makes it insufficiently informative as a marker. For this reason, we undertook to further differentiate the T235 carrier state by constructing haplotypes with alleles in the 5' upstream region of AGT. One such haplotype, -1074t;T235, showed a significant association with angiotensinogen level in a cohort of black and white children and adolescents (76 blacks, mean age = 12.3 +/- 2.0 [SD] years; 139 whites, mean age = 12.4 +/- 1.8 years). With a linear regression model, the level of serum angiotensinogen was significantly related to body mass index (P = .0017) and the haplotype (P = .0001). Within specific race groups, the haplotype was significantly related to serum angiotensinogen in both the blacks (P = .0277) and whites (P = .0001). The mean level of angiotensinogen was higher in the blacks carrying a single copy of the haplotype than in those without the haplotype (1472.2 +/- 68.4 versus 1274.9 +/- 46.7 nmol angiotensin I/L), a difference that was marginally significant (P = .0609). In the whites, the level of angiotensinogen was also higher in carriers of a single copy than in those with no copy (1527.9 +/- 71.2 versus 1099.2 +/- 20.1 nmol angiotensin I/L) (P = .0003). Serum angiotensinogen level did not increase with two copies of the haplotype, but in each racial group, there were only four individuals who were homozygous. The haplotype showed a marginally significant relation (P = .0757) to the mean of longitudinally determined diastolic pressures adjusted for body mass index, race, sex, and age. In summary, using a haplotype to differentiate further the T235 carrier state, we observed an association of genotype with serum angiotensinogen level and blood pressure in blacks and whites. The findings suggest that AGT may play an important role in blood pressure regulation in both racial groups.

Topics: Adolescent; Alleles; Angiotensinogen; Black People; Blood Pressure; Child; Female; Humans; Hypertension; Male; White People

To examine whether the angiotensinogen M235T and angiotensin converting enzyme insertion/deletion (I/D) variants are related to the severity of hypertension in patients with established essential hypertension.. A cross-sectional study.. The hypertension clinic of the Benjamin Franklin University Hospital, Free University of Berlin.. Three hundred and forty-three consecutive Caucasian patients who presented with treated or untreated (n = 115) hypertension were enrolled into the study. Twenty-two patients were excluded from analysis because they had secondary hypertension.. Angiotensinogen M235T and angiotensin-converting enzyme I/D genotypes, 24 h ambulatory blood pressure values, the number of antihypertensive medications administered and left ventricular dimensions assessed by two-dimensional echocardiography.. Neither the angiotensinogen nor the angiotensin converting enzyme genotype was related significantly to the average ambulatory blood pressure and left ventricular dimensions in hypertensives. Furthermore, neither the number of antihypertensive medications administered to treated patients nor blood pressure levels in untreated patients (n = 115) differed significantly between the genotypic groups.. These results do not support the hypothesis that the studied molecular variants of the renin-angiotensin system may represent clinically useful markers of the severity of hypertension in Caucasians with established essential hypertension.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Cross-Sectional Studies; Female; Genetic Markers; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Renin-Angiotensin System

We evaluated the association among the M235T and T174M variants of the angiotensinogen (AGT) gene, plasma AGT, and hypertension status in a sample of Nigerians.. Participants were selected from the extremes of the blood pressure distribution obtained from the population survey of 2509 men and women aged 25 to 74 years. Cases (hypertensive subjects) were individuals who had high blood pressure or were taking antihypertensive medication, and control subjects were individuals with low blood pressure who had never taken antihypertensive medication. We found a significant association between the M235T variant and plasma AGT level. Hypertensive subjects had higher plasma AGT levels compared with control subjects. The allele frequencies of the two variants were similar in the hypertensive patients and the control subjects.. The consistent relationships observed between the M235T variant and the protein product and between plasma level of the protein and hypertension status in different ethnic groups provide some evidence for a biochemical mechanism linking DNA variation in the renin-angiotensin system with the hypertension phenotype.

Topics: Adult; Aged; Alleles; Angiotensinogen; Female; Gene Frequency; Genes; Genetic Variation; Humans; Hypertension; Male; Middle Aged; Nigeria

1. Essential hypertension is characterized by increased vascular resistance due to narrowing of the small arterioles. This may be influenced by vasoactive substances, cell growth and vascular remodelling. 2. A sample of Australian hypertensive and normotensive subjects was investigated for association with genetic markers which are candidates for a role in blood pressure (BP) regulation due to potential effects on vascular diameter. 3. The six markers used were for genes encoding vasoconstrictors, growth factors and a structural protein of the extracellular matrix. 4. No significant association of any of the markers used was found with BP status in this sample of patients.

Topics: Aged; Angiotensinogen; Australia; Disease Susceptibility; Elastin; Female; Genes; Humans; Hypertension; Kallikreins; Male; Middle Aged; Receptor, Insulin; Receptors, Angiotensin; Receptors, Somatomedin

Compared to office measurements, ambulatory monitoring is a more accurate method of blood pressure (BP) characterization and may therefore be useful in a genetics study of hypertension. We studied the relation between the M235T polymorphism of the angiotensinogen gene and hypertension using office and ambulatory (BP) measurements. We enrolled untreated subjects (33 men and 17 women) who were referred for evaluation of office BP >140/90 mm Hg on at least two separate occasions. The M235T genotypes of the angiotensinogen gene were determined by polymerase chain reaction (PCR) amplification of DNA extracted from peripheral blood leukocytes and digested with BSTU1. The distribution of the genotypes were MM = 0.22, MT = 0.44, TT = 0.34. Based on office measurements, a significant difference in diastolic blood pressure (BP) was detected only between the TT and the MT genotype subjects (office BP: MM = 150 +/- 25/97 +/- 13 mm Hg, MT = 147 +/- 23/ 95 +/- 13 mm Hg, TT = 161 +/- 25/104 +/- 15 mm Hg). By contrast, with ambulatory BP monitoring, both systolic and diastolic blood pressures were significant higher in TT versus MM and MT (ambulatory BP, MM = 138 +/- 10/88 +/- 9 mm Hg, MT = 141 +/- 15/89 +/- 11 mm Hg, TT = 152 +/- 18/97 +/- 12 mm Hg). Covariate analysis revealed an independent relationship between the M235T genotype and systolic, diastolic, and mean ambulatory BP. Ambulatory monitoring improved the analytic power of our study and allowed detection of a clear and consistent relationship between angiotensinogen polymorphism and hypertension with a relatively small sample size.

Topics: Adult; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

The present study was designed to investigate the development of atherosclerotic lesions in hypertensive transgenic mice carrying both the human renin and angiotensinogen genes (Tsukuba hypertensive mice; THM). THM and C57BL/6J control mice 2 to 3 months of age were fed with either an atherogenic or a normal diet for 14 weeks. Although the systolic blood pressure of either strain remained the same regardless of diet, it was significantly higher in THM than in C57BL/6J on both diets. Total plasma cholesterol concentrations in mice on the atherogenic diet were significantly higher than those in mice fed the normal diet. Lipoprotein profiles of cholesterol in THM were fundamentally similar to those in C57BL/6J on either the atherogenic or normal diet. Compared with controls, however, microscopic analyses revealed accelerated damage of cellular structure in the aortic root in THM fed with the atherogenic diet. Remarkably, the surface area of atherosclerotic lesion in THM was shown by quantitative image analysis to be 4 times larger than that in C57BL/6J on the same atherogenic diet. These findings suggested that hypertension induced by the activated renin-angiotensin system is involved in the development of atherosclerotic lesions. Therefore, THM should be a useful animal model for the study on the pathogenesis of atherosclerosis.

Topics: Angiotensinogen; Animals; Aorta; Arteriosclerosis; Blood Glucose; Blood Pressure; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Female; Humans; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Renin; Renin-Angiotensin System

The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Cancasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)n alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)16 explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-6A polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.

Topics: Age of Onset; Angiotensinogen; Databases, Factual; DNA Primers; Exons; Female; France; Gene Frequency; Genetic Variation; Genotype; Haplotypes; Humans; Hypertension; Japan; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Utah

To determine whether angiotensinogen (AGT) and angiotensin II type 1 (AT1) receptor genes contribute to the development of arterial hypertension in members of French Caucasian families and in subjects with hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM).. Sibpair linkage analyses were performed with microsatellites near the AGT and AT1 receptor genes in 179 hypertensive sibpairs from 69 NIDDM kindreds. In addition, population/association studies were performed with the M235T and T174M polymorphisms of the AGT gene, and the A1166C polymorphism of the AT1 receptor gene.. No evidence for linkage between the AGT and AT1 receptor loci and hypertension was observed. In addition, the distributions of genotypes of AGT and AT1 receptor gene polymorphisms did not differ significantly among a group of unrelated individuals with both hypertension and NIDDM (n = 188) and three groups of unrelated control subjects with NIDDM (n = 117), hypertension (n = 75) or none of these conditions (n = 125).. These results suggest that the AGT and AT1 receptor genes are not major genetic determinants of hypertension associated with NIDDM in this population, although we can not exclude the possibility that these loci make a minor contribution in a polygenic context.

Topics: Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Genetic Linkage; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

To examine the association of the molecular variants of the angiotensinogen (AGT) gene with essential hypertension in Taiwanese.. We conducted a case-control study concerning 151 subjects, 102 hypertensives and 49 normotensives. We created a rapid mini-sequencing method based on dye-terminator cycle sequencing to simultaneously detect the M235T and T174M variants of the AGT gene for each subject.. The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (chi 2 = 11.106, P = 0.004 and chi 2 = 6.453, P = 0.011, respectively), whereas those of the T174M variant did not differ (chi 2 = 0.004, P = 0.998 and chi 2 = 0.032, P = 0.858, respectively). The odds ratio for hypertension was 3.64 (95% confidence interval 1.56-8.49) for subjects with the C/C genotype of the M235T variant compared with other genotypes of 2.87 (95% confidence interval 1.76-4.68) for those carrying allele C versus those carrying allele T.. The molecular variant M235T, but not T174M, of the AGT gene is associated significantly with essential hypertension in this Taiwanese population. The genotype C/C or allele C is a risk factor for hypertension. The underlying mechanism of this association needs to be elucidated further.

Topics: Adult; Aged; Alleles; Amino Acid Sequence; Angiotensinogen; Base Sequence; Case-Control Studies; DNA; DNA Primers; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Odds Ratio; Polymerase Chain Reaction; Taiwan

Wistar fatty rats (WFR) show obesity and obesity-related features, including hypertension. In this study, we examined the expression of angiotensinogen mRNA in a variety of tissues at different times in WFR and control Wistar lean rats (WLR). WFR were obese and hypertensive at 16 and 24 wk. Plasma renin activity and plasma angiotensinogen concentration showed age-dependent increases in WFR but decreases in WLR. Northern blot analysis showed no significant differences in the levels of hepatic and renal angiotensinogen mRNA between WFR and WLR, and the levels of fat and adrenal angiotensinogen mRNA were lower in WFR than in WLR. On the other hand, the levels of cardiac angiotensinogen mRNA at 16 and 24 wk and those of aortic angiotensinogen mRNA at 16 wk were significantly higher in WFR than in WLR. These results show that the expression of tissue angiotensinogen mRNA is regulated differently in WFR and WLR and indicate that the development of hypertension in WFR is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as in cardiac and aortic angiotensinogen mRNA. Moreover, these results suggest the existence of obesity hypertension-linked and tissue-specific regulation of angiotensinogen gene expression.

Topics: Angiotensinogen; Animals; Female; Gene Expression; Hypertension; Obesity; Rats; Rats, Wistar; Reference Values; Renin-Angiotensin System; RNA, Messenger; Tissue Distribution

The effects of chronic treatment with an angiotensin II receptor antagonist, candesartan cilexetil (TCV-116, 0.1, 1, 10 mg/kg), and an angiotensin converting enzyme inhibitor, enalapril maleate (enalapril, 10 mg/kg), on the development of end-organ damage were examined in stroke-prone spontaneously hypertensive rats (SHRSP). The control SHRSP developed severe hypertension with stroke signs and increased urinary protein excretion. TCV-116 (0.1 mg/kg) reduced the stroke incidence and urinary protein excretion without affecting the blood pressure. TCV-116 (1 and 10 mg/kg) and enalapril reduced blood pressure, the stroke incidence, the urinary indices and left ventricular weight. Circulating renin-angiotensin system (RAS) and renal renin mRNA expression were significantly accelerated or tended to be accelerated in the control SHRSP with end-organ damages. A low dose of TCV-116 tended to reduce the RAS indices in plasma by improving the damages, whereas a high dose (10 mg/kg) increased them by the reflexes with blocking RAS. The present results indicate that chronic All blockade reduces the increase in blood pressure, end-organ damages and RAS related to the damages in SHRSP.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiomegaly; Cerebrovascular Disorders; Enalapril; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Renin; RNA, Messenger; Tetrazoles

We examined the association between variants in the core promoter element 1 (AGCE1) of the human angiotensinogen gene (AGT), which acts as a critical regulator of AGT transcription, and the risk for hypertension. One hundred and eighty patients with documented essential hypertension and a family history of hypertension and 194 control subjects without hypertension were selected and frequency matched by age and sex. Genomic DNA from leukocytes was analyzed for genetic variants (position: -20 to -18) in AGCE1. The haplotype in AGCE1 was significantly associated with increased risk of essential hypertension (P<.05). The frequency of subjects with homozygous C allele at position -18(CC/C-18T) was significantly higher in case patients than in control subjects (P<.005), and the evaluated odds ratio for hypertension was 4.2 (95% confidence interval [CI]: 1.4 to 12.8, CC/C-18T versus CT/C-18T). The homozygous threonine allele at codon 235 (TT/M235T) in exon 2 of AGT was also associated with hypertension (P<.02; odds ratio, TT versus other genotypes, 1.8; 95% CI, 1.1 to 2.7). According to haplotype analysis between AGT polymorphisms, we identified linkage disequilibrium between M235T and A-20C and between M235T and C-18T. We conclude that C-18T polymorphism in AGCE1 is a genetic risk factor for essential hypertension in the Japanese and is more tightly and directly associated with hypertension than TT/M235T.

Topics: Aged; Alleles; Angiotensinogen; Asian People; Base Sequence; Case-Control Studies; Female; Gene Frequency; Genetic Linkage; Genetic Variation; Genotype; Humans; Hypertension; Japan; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic; Reference Values; Risk Factors

Essential hypertension has been linked to a highly polymorphic marker at the angiotensinogen locus, and association with a polymorphism in this locus has been found in some populations. We tested the hypothesis that these same polymorphic markers are linked to essential hypertension in Mexican Americans. The data comprised all the affected relative pairs in 46 extended families chosen at random from a low-income barrio in San Antonio. Specifically, we searched for linkage by testing for excessive marker alleles shared identical by descent (IBD) among hypertensive relative pairs. When women taking oral contraceptives or hormones were excluded, the affected relative pairs shared a significant excess of alleles IBD for the highly heterozygous GT repeat polymorphism (P=.038) and were marginally significant for the M235T variant (P=.079), which has a much lower heterozygosity (0.43 versus 0.85 for the GT repeat). We also assayed plasma levels of angiotensinogen and, using likelihood methods, found no significant association (P=.43) between plasma levels of angiotensinogen and M235T genotypes. These results support the linkage of essential hypertension to the angiotensinogen locus but do not indicate a specific role for the M235T variant.

Topics: Adult; Angiotensinogen; Body Mass Index; Chromosome Mapping; Dinucleotide Repeats; Female; Genetic Linkage; Genetic Variation; Genotype; Humans; Hypertension; Male; Mexican Americans; Middle Aged; Polymorphism, Genetic

There is now convincing evidence that various tissues express their own tissue renin-angiotensin system, which may be regulated independently of the systemic renin-angiotensin system. However, little information is available on the regulation of the tissue renin-angiotensin system. We investigated the regulation of tissue angiotensinogen gene expression with respect to the development of hypertension. We measured basal and lipopolysaccharide-stimulated plasma angiotensinogen concentrations by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 4 and 13 weeks of age. Basal plasma angiotensinogen concentration in SHR was comparable to that in WKY at 4 weeks of age and was significantly higher than that in WKY at 13 weeks of age. Lipopolysaccharide induced a significant increase in plasma angiotensinogen concentration in both WKY and SHR at 4 and 13 weeks of age. At 4 weeks of age, the basal levels of angiotensinogen mRNA in the liver, fat, adrenal, and aorta were higher in WKY than in SHR. At 13 weeks of age, the basal levels of angiotensinogen mRNA in the fat, adrenal, aorta, spleen, and kidney were higher in WKY than in SHR, while that in the liver did not differ significantly between the two strains. At 4 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, fat, adrenal, and aorta in both WKY and SHR. At 13 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, aorta, and adrenal; decreased those in the spleen; and had no effect in the kidney in both WKY and SHR. Interestingly, lipopolysaccharide increased the angiotensinogen mRNA level in fat only in SHR, with no effect in WKY, at 13 weeks of age. Lipopolysaccharide stimulated tumor necrosis factor-a mRNA expression in fat of WKY and SHR, and the increase in tumor necrosis factor-alpha mRNA level in SHR was significantly greater than that in WKY. Therefore, the increased tumor necrosis factor-alpha mRNA expression may be involved in the increased lipopolysaccharide-induced expression of angiotensinogen gene in fat of SHR at 13 weeks of age. These data suggest that the transcriptional and probably posttranscriptional regulation of angiotensinogen mRNA differs between SHR and WKY, that the regulation of angiotensinogen gene expression is tissue-specific, and that the altered expression

Topics: Angiotensinogen; Animals; Gene Expression; Hypertension; Lipopolysaccharides; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; Tumor Necrosis Factor-alpha

The angiotensinogen (AGT) gene M235T variant is associated with essential hypertension and elevated plasma AGT concentrations, although the underlying mechanisms are unknown. Recent studies have suggested that AGCE 1 (human AGT gene core promoter element 1) located in the 5' upstream core promoter region (position -25 to -1) of the human AGT gene has an important part in the expression of AGT mRNA by binding with transcription factor AGCF 1 (human AGT gene core promoter element binding factor 1), and a mutation at -20 from adenine to cytosine (A-20C) increases the level of expression of this transcript. We therefore examined subjects with this mutation to study the association with increased plasma AGT concentrations and with essential hypertension. One hundred eighty-eight subjects receiving no antihypertensive medication were examined with regard to the correlation between A-20C and plasma AGT concentrations, and 234 subjects were studied with respect to the association between A-20C and essential hypertension. A-20C was determined by polymerase chain reaction-restriction fragment length polymorphism analysis with EcoOR 109I. Multiple regression analysis showed a weak but significant correlation between A-20C and plasma AGT concentrations (P=.047) and essential hypertension (P=.049). The results suggest that A-20C may underlie the increase in plasma AGT concentrations and be involved in the development of essential hypertension.

Topics: Angiotensinogen; Blood Pressure; Cholesterol; Cholesterol, HDL; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; Middle Aged; Odds Ratio; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic; Reference Values; RNA, Messenger; Transcription Factors; Transcription, Genetic; Triglycerides

The spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components.

Topics: Aging; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Atrial Natriuretic Factor; Captopril; Cardiomegaly; Gene Expression Regulation; Heart; Heart Failure; Hypertension; Male; Myosin Heavy Chains; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta

The homozygous deletion allele of the angiotensin converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the epsilon4 allele of the apolipoprotein E gene (apoE/epsilon4) are reported to be associated with ischemic heart disease. Cerebrovascular disease (CVD) is another atherosclerotic disease; and the effects of these polymorphisms on CVD have been confusing. In this study, we investigated whether ACE/DD, AGN/TT, and apoE/epsilon4 genotypes are associated with CVD and whether genetic risk is enhanced by the effect of one upon another. We ascertained these genotypes in patients with cerebral infarction (n = 55) and cerebral hemorrhage (n = 38), diagnosed by brain computed tomography. Control subjects for the infarction group and the hemorrhage group were randomly selected from 583 subjects matched for age, gender, and history of hypertension with patients. Frequency of ACE/DD genotype was higher in the patients with infarction than in the controls (chi2 = 6.1, P < .05). The AGN/TT genotype was not associated with either infarction or hemorrhage, but it increased the relative risk for cerebral infarction in the subjects with ACE/DD genotype (chi2 = 8.0, P < .01, odds ratio; 11.7, 95% confidence intervals: 1.4 to 96.0). There was no significant association between apoE/epsilon4 and CVD. These results suggest that ACE/DD predicts cerebral infarction, but not cerebral hemorrhage, and that AGN/TT enhances the risk for cerebral infarction associated with ACE/DD.

Topics: Adult; Aged; Angiotensinogen; Apolipoproteins E; Cerebrovascular Disorders; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

In this study, to investigate the mechanism of hypertension-associated induction of cardiac angiotensinogen in vivo and in vitro, we studied the regulation of angiotensinogen mRNA in the hearts of genetically hypertensive rats and in the rat cardiomyocytes. Levels of cardiac angiotensinogen mRNA were significantly increased in the hypertensive rats. Steady state mRNA levels for angiotensinogen mRNA in cardiomyocytes were increased by angiotensin II and mechanical stretch. The addition of an angiotensin II type 1 receptor antagonist (CV11974) and a transcriptional inhibitor (actinomycin D) completely blocked the induction of angiotensinogen mRNA by angiotensin II in cardiomyocytes. The addition of CV11974 significantly, but not completely, inhibited the induction of angiotensinogen mRNA by mechanical stretch. Actinomycin D completely blocked the induction of angiotensinogen mRNA by stretch in cardiomyocytes. An angiotensin II type 2 receptor antagonist (PD123319) and a protein synthesis inhibitor (cycloheximide) did not affect the induction. These results indicate that the expression of cardiac angiotensinogen mRNA is activated by the development of hypertensive cardiac hypertrophy, and that angiotensin II and mechanical stretch activates the angiotensinogen gene via the angiotensin II type 1 receptor-pathway in cardiomyocytes.

Topics: Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Cells, Cultured; Dactinomycin; Hypertension; Myocardium; Nucleic Acid Synthesis Inhibitors; Rats; Rats, Inbred SHR; Rats, Wistar; RNA, Messenger; Stress, Mechanical; Tetrazoles; Transcription, Genetic; Up-Regulation

Results of recent genetic studies suggest that the angiotensinogen gene is a possible determinant of hypertension. Using antisense technology, we demonstrated that generation of circulating angiotensinogen is a rate-limiting step in blood pressure regulation. In the present study, we examined how the angiotensinogen gene is regulated in vivo. The transcriptional cis-elements, angiotensinogen gene-activating elements (AGE) 2 and 3, have been reported to regulate angiotensinogen production in human hepatocytes in vitro. To determine the critical transcriptional regulator of angiotensinogen production in vivo, we used synthetic double-stranded oligodeoxynucleotides (ODN) as "decoy" cis-elements to block the binding of nuclear factors to promoter regions of the targeted gene, resulting in the inhibition of gene transactivation. Here we examined whether AGE 2 and AGE 3 in the promoter region of the angiotensinogen gene have a pivotal role in hepatic angiotensinogen production in vivo. Hepatic angiotensinogen mRNA was decreased by the transfection of AGE 2 but not mismatched decoy ODN. Transfection of decoy but not mismatched ODN against AGE 2 resulted in a transient decrease in blood pressure of spontaneously hypertensive rats (SHR), accompanied by a reduction in plasma angiotensinogen and angiotensin II levels. In contrast, transfection of AGE 3 decoy ODN had little effect on blood pressure. Overall, our results demonstrate that transfection of decoy ODN against AGE 2, but not against AGE 3, of the angiotensinogen gene resulted in a transient decrease in high blood pressure of SHR, suggesting that the transcriptional cis-element AGE 2, rather than AGE 3, has an important role in blood pressure regulation through the control of circulating angiotensinogen.

Topics: Angiotensinogen; Animals; Base Sequence; Blood Pressure; Hypertension; Male; Molecular Sequence Data; Oligonucleotides; Rats; Transcription Factors; Transcriptional Activation

To examine the utility of rats transgenic for human angiotensinogen in the study of human renin-induced hypertension, we first developed assays to measure both the human and rat renin-angiotensin systems in these rats. We used human and mouse renin, transgenic human angiotensinogen, and the human renin inhibitor Ro 42-5892 to determine human- and rat-specific plasma angiotensinogen concentrations, renin activity, and renin concentration. The assays were validated with rat and human plasma mixed in known amounts and with plasma from rats transgenic for human renin. We then tested the human angiotensinogen-transgenic rats by infusing recombinant human renin over 10 days (50 ng/h, n=4) with osmotic minipumps. High human angiotensinogen transgene expression was found in the liver, brain, kidney, gastrointestinal tract, and aorta, whereas rat angiotensinogen gene expression was detected in the liver and brain. During human renin infusion, blood pressure increased to >200/150 mm Hg. Before infusion, human angiotensinogen was 100-fold greater than rat angiotensinogen (141 +/- 73 versus 1.2 +/- 0.16 microg angiotensin l/mL); the relation was not changed by renin infusion. Plasma renin activity increased 300-fold; human plasma renin concentration increased to very high levels (449 +/- 262 ng of angiotensin I per mL per hour), whereas rat plasma renin concentration decreased to undetectable levels. Thus, chronic human renin infusion resulted in severe hypertension with extreme plasma renin activity and plasma renin concentration. However, even at these levels, human angiotensinogen was not rate limiting and angiotensin II was not a significant stimulus for angiotensinogen production. We conclude that these transgenic rats represent a novel model of human renin-dependent hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Humans; Hypertension; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renin

Within the context of an international collaborative study of the evolution of hypertension in the black diaspora, we determined the allelic distribution of hypertension candidate genes for the renin-angiotensin system in three populations of African origin. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and the M235T and T174M variants of the angiotensinogen (AGT) gene were examined in individuals from Nigeria, Jamaica, and the United States. Large differences in the prevalence of hypertension were recorded in door-to-door surveys, ranging from 16% in Nigeria to 33% in the United States. The frequency of the D allele was similar in all groups (54%, 59%, and 63% in Nigeria, Jamaica, and the United States, respectively). The 235T allele of the AGT gene was found in 81% of US and Jamaican blacks and 91% of Nigerians; very little variation was seen for the T174M marker. Despite large differences in hypertension rates, genetic variation at the index loci among these groups was modest. Overall, the frequency of the ACE*D allele was only slightly higher than that reported for European and Japanese populations, whereas the AGT 235T allele was twice as common. Compared with blacks in the western hemisphere, Nigerians had a higher frequency of the 235T allele, which is consistent with 25% European admixture in Jamaica and the United States. The results indicate the potential for etiologic heterogeneity in genetic factors related to hypertension across ethnic groups while suggesting that environmental exposures most likely explain the gradient in risk in the comparison among black populations.

Topics: Alleles; Angiotensinogen; Black or African American; Black People; Humans; Hypertension; Jamaica; Nigeria; Peptidyl-Dipeptidase A; Polymorphism, Genetic; United States

We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.

Topics: Angiotensinogen; Animals; Baroreflex; Heart Rate; Hypertension; Mice; Mice, Transgenic; Pressoreceptors; Renin

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.

Topics: Adult; Alleles; Angiotensinogen; Base Sequence; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Genetic Predisposition to Disease; Humans; Hypertension; Molecular Probes; Molecular Sequence Data; Polymorphism, Genetic

Common molecular variants of the angiotensinogen gene have been associated with human hypertension. The rare Tyr to Cys change at residue 248 of mature angiotensinogen was identified in one pedigree. Heterozygous individuals (Y248C) had a 40% decrease in plasma angiotensinogen concentration and a 35% reduction of the angiotensin I production rate. Recombinant wild-type (Tyr-248) and mutant (Cys-248) proteins were stably expressed in Chinese hamster ovary cells. Angiotensinogen monoclonal antibodies revealed marked differences in the epitope recognition of the mutant protein and allowed the demonstration of its presence in plasma of Y248C individuals. Similar kinetic constants of angiotensin I production with human renin were observed for both proteins. Western blot analysis showed similar heterogeneities; however, a 3-kDa increase in molecular mass for the Cys-248 protein was observed after immunopurification. Metabolic labeling of the intracellular Cys-248 protein showed a 61-kDa band in addition to the 55.5- and 58-kDa bands observed for the Tyr-248 protein, with all bands being sensitive to endoglycosidase H. In addition, pulse-chase studies revealed a slower intracellular processing for the Cys-248 protein. In conclusion, the Cys-248 mutation alters the structure, glycosylation, and secretion of angiotensinogen in Chinese hamster ovary cells and is accompanied by a decrease in plasma angiotensinogen concentration in Y248C individuals.

Topics: Amino Acid Sequence; Angiotensinogen; Base Sequence; Cysteine; Female; Genetic Carrier Screening; Genetic Variation; Glycoside Hydrolases; Glycosylation; Humans; Hypertension; Immunoradiometric Assay; Male; Molecular Sequence Data; Oligodeoxyribonucleotides; Pedigree; Point Mutation; Radioimmunoassay; Recombinant Proteins; Tyrosine

Angiotensinogen is expressed in many tissues besides the liver. Recent studies have suggested that abnormalities in the regulation of angiotensinogen gene expression may be involved in the development of hypertension. However, little information is available concerning the functional significance of tissue angiotensinogen. In this study, we measured plasma angiotensinogen concentration by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of age in SHR and became higher than that in WKY. The levels of hepatic angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic, adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6 and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On the other hand, cardiac and fat angiotensinogen mRNA levels were significantly increased at 14 weeks of age in SHR. These results demonstrate that the expression of tissue angiotensinogen is regulated differently in SHR and WKY and indicate that the development of hypertension is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as cardiac and adipogenic angiotensinogen mRNA in SHR.

Topics: Angiotensinogen; Animals; Blood Pressure; Blotting, Northern; Gene Expression Regulation; Hypertension; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Species Specificity

We administered liposome-encapsulated antisense oligodeoxynucleotide targeted to angiotensinogen mRNA peripherally to spontaneously hypertensive rats to test whether peripheral angiotensinogen reduction would lower their hypertensive blood pressures and to determine the role of peripheral angiotensinogen in the modulation of hypertension. Using in vitro translation techniques, we tested the sequence specificity of the antisense sequence. The selected antisense sequence decreased angiotensinogen production in vitro, enabling us to distinguish between specific and nonspecific effects. To increase the efficiency of peripheral and hepatic antisense delivery, oligonucleotides were liposome encapsulated and intra-arterial administration. Confocal microscopy was used for determination of the hepatic distribution of fluorescently labeled antisense. Encapsulated antisense molecules were seen to be distributed within liver tissue 1 hour after injection; however, little or no uptake was observed with the unencapsulated oligonucleotides. We also determined the physiological effects of antisense oligodeoxynucleotide targeted to liver angiotensinogen mRNA. Administration of liposome-encapsulated antisense significantly decreased hypertensive blood pressures to normotensive levels compared with scrambled control oligonucleotides, unencapsulated antisense, and empty liposomes (P = .013). These data were supported by biochemical changes elicited by the antisense treatment. Rats receiving liposome-encapsulated antisense had significantly lowered peripheral angiotensinogen and angiotensin II levels compared with control groups (P < .05). No significant heart rate changes were observed in the antisense or control groups. These results suggest that peripheral angiotensinogen plays a role in the maintenance of hypertensive blood pressure in this model of hypertension and that peripheral administration of antisense molecules is possible with organ-targeted delivery mechanisms.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Data Interpretation, Statistical; Drug Carriers; Hypertension; In Vitro Techniques; Liposomes; Liver; Male; Oligonucleotides, Antisense; Protein Biosynthesis; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic

To examine the association between blood pressure, angiotensinogen levels, angiotensin converting enzyme activity and polymorphisms of the angiotensinogen and angiotensin converting enzyme genes in a population-based sample.. Five hundred participants were recruited in a house-to-house survey of three communities in metropolitan areas of Kingston and St Andrew, in Jamaica. Demographic data, anthropometric and blood pressure measurements were obtained for each participant during a brief clinic visit. Circulating levels of angiotensinogen and angiotensin converting enzyme activity were measured in venous blood samples. Polymorphisms of the angiotensinogen and angiotensin converting enzyme genes were determined.. A weak association between angiotensinogen level, angiotensin converting enzyme activity and blood pressure was identified in this population, but substantial joint effect of angiotensin converting enzyme activity and angiotensinogen level on blood pressure was apparent. Variants of the angiotensinogen gene had inconsistent effects on blood pressure and on the risk of hypertension. Angiotensinogen level and angiotensin converting enzyme activity were significantly related to several measures of obesity, including body mass index, waist circumference and skin fold thickness.. The angiotensinogen and angiotensin converting enzyme genetic variants which were studied appear to have only a modest relationship with blood pressure and associated anthropometric risk factors among blacks.

Topics: Adult; Aged; Angiotensinogen; Base Sequence; Black People; Blood Pressure; Female; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Peptidyl-Dipeptidase A

Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235 --> threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II.. Hypertensive (n = 34, all off medication) and normotensive (n = 57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration.. After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P = 0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P = 0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response.. Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.

Topics: Adolescent; Adult; Angiotensin II; Angiotensinogen; Base Sequence; Blood Pressure; Body Mass Index; Female; Genotype; Homozygote; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Molecular Sequence Data; Obesity; Oligonucleotide Probes; Pedigree; Renal Artery; Renal Plasma Flow; Vascular Resistance; Vasoconstrictor Agents

Plasma angiotensinogen is elevated in essential hypertensives and shows a strong correlation with blood pressure. Patients with hypertension often display insulin resistance and we have found previously an association of a RsaI RFLP in intron 9 of the insulin receptor gene (INSR) with hypertension. Since insulin resistance is accompanied by hyperinsulinaemia and insulin can stimulate angiotensinogen production, we hypothesized that hypertension-associated genotypes of INSR may be associated with elevation in plasma angiotensinogen. We used PCR to detect a NsiI RFLP in exon 8 of INSR and examined its relationship with plasma angiotensinogen, as well as hypertension, in 134 Caucasian hypertensives with two hypertensive parents and in 126 normotensives. Plasma angiotensinogen tracked weakly with the major allele of the NsiI RFLP in hypertensives (p = 0.08). Moreover, the frequency of this allele was higher in lean hypertensives than in lean normotensives (p < 0.05) and in normolipidaemic hypertensives than normolipidaemic normotensives (p < 0.02). The present study thus suggests that there could be a relationship of plasma angiotensinogen with INSR genotype, and of each with hypertension.

Topics: Alleles; Analysis of Variance; Angiotensinogen; Blood Pressure; Deoxyribonucleases, Type II Site-Specific; Exons; Female; Genotype; Humans; Hypertension; Lipids; Male; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Receptor, Insulin; Renin; White People

Recent studies have suggested that an inherited predisposition to essential hypertension may increase susceptibility to nephropathy for patients with IDDM. Essential hypertension has been linked to the angiotensinogen (AGT) gene in genetic linkage studies in American and European populations. A molecular variant (M235T), which has a functional effect, has been described with highest plasma AGT levels being associated with the TT genotype. In a case-control study, we have evaluated the role of this functional genetic marker in patients with IDDM and nephropathy and in IDDM patients without nephropathy. We studied 195 IDDM patients, of whom 95 had established diabetic nephropathy; the remaining 100 patients, who had no evidence of microalbuminuria, served as control subjects. All patients were whites born in Northern Ireland. The point mutation in the AGT gene was analyzed using restriction typing. The background frequency of the M235T variant was assessed in 80 healthy blood donors, and the TT genotype was present in 9%. This genotype occurred in 8% of control IDDM patients without nephropathy and 19% of IDDM patients with nephropathy (P = 0.025). The odds ratio for diabetic nephropathy associated with the TT genotype was 2.7 (95% CI 1.04-7.52). There was no relationship between blood pressure and AGT genotypes in the control group. We cannot exclude the possibility that the observed association in the nephropathy group is due to an association between AGT genotype and hypertension. This evidence may help to explain the predisposition to diabetic nephropathy afforded by hypertension and merits further investigation.

Topics: Adult; Age of Onset; Albuminuria; Angiotensinogen; Base Sequence; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; DNA Primers; Female; Genetic Variation; Genotype; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Reference Values; Restriction Mapping

Plasma angiotensin-converting enzyme (ACE) tracks with the deletion allele of an insertion/deletion (I/D) polymorphism of the ACE gene. The aim of the present study was to determine plasma renin and angiotensinogen for each ACE genotype in 54 hypertensive and 96 normotensive subjects. Plasma renin was reduced by 52 +/- 15 S.E.% in DD and by 24 +/- 12% in ID hypertensives when compared to II hypertensives (P < 0.05 by one-way ANOVA), but in the normotensive subjects, renin values were similar for each genotype. Plasma angiotensinogen did not differ across ACE genotypes, but was elevated by 25 +/- 3 S.E.% in hypertensives and showed a significant correlation with blood pressure. In conclusion, although renin does not differ significantly between ACE genotypes of normotensives, a reciprocal relationship may exist between plasma renin and plasma ACE in hypertensives.

Topics: Adult; Angiotensinogen; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin; Renin-Angiotensin System

We attempted to apply FISH to chromosomal mapping of the human angiotensinogen (hAG) and human renin (hRN) transgenes which are carried by the parental strains of the Tsukuba hypertensive mouse. We report here that the hAG gene is mapped in the C2 region of Chr 19 and the hRN gene in the A1 region of Chr 6.

Topics: Angiotensinogen; Animals; Chromosome Mapping; DNA; Female; Genetic Linkage; Humans; Hypertension; In Situ Hybridization, Fluorescence; Karyotyping; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Renin

A recent study reported a significant relationship between a T704-->C (Met235-->Thr) variant in exon 2 of the angiotensinogen gene in adults and essential hypertension. In the present study, this variant was detected in 131 Japanese children using a polymerase chain reaction. The allele frequency of the variant was 0.76. The genotype frequency of the homozygote for the allele was 0.59, and children who were homozygous had higher systolic blood pressure than those with the other two genotypes. No relationship was found between children's polymorphism and a family history of essential hypertension. These findings suggest that this molecular variant of the angiotensinogen gene may play some role in the regulation of blood pressure in Japanese children.

Topics: Angiotensinogen; Blood Pressure; Child; Female; Gene Frequency; Genetic Variation; Humans; Hypertension; Japan; Male; Polymerase Chain Reaction; Regression Analysis

Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.

Topics: Angiotensin II; Angiotensinogen; Animals; Biphenyl Compounds; Hypertension; Imidazoles; Kidney; Losartan; Male; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin; Tetrazoles

The angiotensinogen gene has been linked to the development of essential hypertension, and a M235T variant of this gene, associated with increased plasma levels of angiotensinogen, is more common in hypertensives than in normotensive controls in various populations. The present study was conducted to examine whether the M235T variant of the angiotensinogen gene may be a risk factor for the development of hypertension in patients undergoing renal transplantation.. DNA for genetic analysis was prospectively collected from 269 consecutive patients undergoing kidney transplantation between 1988 and 1993 and their corresponding donors. Presence of hypertension and graft survival was analysed by blinded review of all case records over a follow-up period up to 30 months. Angiotensinogen genotype was determined by a mutagenically separated allele-specific polymerase-chain-reaction technique.. While post-transplant hypertension was present in 78% of all patients, no relationship was found between either donor or recipient genotype and the presence or severity of post-transplant hypertension. Furthermore, there was no relationship between angio-tensinogen genotype and graft survival during the course of the study.. These findings do not support the hypothesis that the M235T variant of the angiotensinogen gene is a risk factor for the development of post-transplant hypertension.

Topics: Adult; Alleles; Angiotensinogen; Female; Gene Frequency; Genetic Variation; Genotype; Graft Survival; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Postoperative Complications

Maternal hypertension is a common complication of pregnancy and its pathophysiology is poorly understood. This phenomenon was studied in an animal model by mating transgenic mice expressing components of the human renin-angiotensin system. When transgenic females expressing angiotensinogen were mated with transgenic males expressing renin, the pregnant females displayed a transient elevation of blood pressure in late pregnancy, due to secretion of placental human renin into the maternal circulation. Blood pressure returned to normal levels after delivery of the pups. Histopathologic examination revealed uniform enlargement of glomeruli associated with an increase in urinary protein excretion, myocardial hypertrophy, and necrosis and edema in the placenta. These mice may provide molecular insights into pregnancy-associated hypertension in humans.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Crosses, Genetic; Disease Models, Animal; Female; Humans; Hypertension; Kidney Glomerulus; Male; Mice; Mice, Transgenic; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Renin

Effects of isoproterenol (ISO) on the expression of cardiac angiotensinogen mRNA, angiotensin converting enzyme (ACE) activity, and mechanical functions in spontaneously hypertensive rats were investigated. In the acute phase, defined as within 24 h after the subcutaneous injection of ISO 85 mg/kg, cardiac angiotensinogen mRNA was slightly induced, but ACE activity was not. In the subacute phase, defined as within 8 d after ISO treatment on 2 successive d, both angiotensinogen mRNA expression and ACE activity in the heart were markedly induced. ACE activity in serum was not affected by ISO in either phase. In the subacute phase, ISO reduced body weight and blood pressure, increased ventricular weight and calcium content, and impaired cardiac mechanical function. Oral treatment with imidapril (10 mg/kg/d), an ACE inhibitor, 1 h before each ISO treatment and on the following 6 d, improved ventricular hypertrophy, the elevation of the left ventricular end diastolic pressure, the reduction in contractility, and the prolongation of the time constant. Imidapril significantly suppressed both serum and cardiac ACE activity but did not affect cardiac angiotensinogen mRNA expression in the subacute phase. These results indicate that enhancement of cardiac angiotensinogen mRNA and ACE activity is involved in ISO-induced cardiac dysfunction. Imidapril improved ISO-induced cardiac dysfunction, possibly by suppression of the local ACE activity as well as circulating ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Cardiotonic Agents; Heart Rate; Hypertension; Imidazoles; Imidazolidines; Isoproterenol; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; RNA, Messenger

We have developed a transgenic animal model to investigate the effects of overexpression of rat prorenin on the cardiovascular system. Two transgenic rat lines were generated in which rat prorenin expression was directed to the liver by a human alpha1-antitrypsin promoter. Liver-specific expression was confirmed by RNase protection assay. Plasma prorenin concentrations in transgenic rats were increased 400-fold in the males of both lines but were increased only two- to threefold in the females. Thus, transgene expression exhibited sexual dimorphism. Blood pressures were not significantly higher in transgenic rats than in nontransgenic controls. The ratio of heart weight to body weight was greater in male transgenic rats than in the nontransgenic controls. Histological analysis revealed severe renal lesions and hypertrophic cardiomyocytes in transgenic males only. This transgenic model demonstrates a likely role of prorenin in the development of cardiac and renal pathology independent of hypertension. These animals will facilitate studies of the effects of blockade of the renin-angiotensin system and other pharmacological interventions on the development and treatment of cardiac, vascular, and renal lesions induced by changes in this system in the absence of chronic hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Base Sequence; Blood Pressure; Cardiovascular Diseases; Enzyme Precursors; Female; Gene Expression; Heart; Hypertension; Kidney; Liver; Male; Molecular Sequence Data; Organ Size; Rats; Rats, Inbred F344; Renin; Risk Factors; RNA, Messenger

There is agreement that a family history of hypertension (HT), is a predictor for the risk of diabetic nephropathy (DN) in patients with type 2 diabetes, and possibly also type 1 diabetes. It follows that genes related to the risk of hypertension must also be considered candidate genes for DN. The 235T allele of the angiotensinogen gene was found to be related to primary HT.. To examine whether it is predictive for DN as well, we examined the angiotensinogen gene polymorphism in 230 healthy local controls, 423 patients with type 1 diabetes (n = 180 with DN; n = 243 without DN) and 663 patients with type 2 diabetes (n = 310 with DN; n = 353 without DN). The angiotensinogen gene M235T polymorphism was determined using PCR amplification.. The following results were obtained (i) no significant difference of genotype distribution (type 1: MM/MT/TT (%) 27.6/57.2/15.2 vs 27.2/56.1/16.7 (P = 0.92); type 2; MM/MT/TT (%) 31.7/48.2/2/20.1 vs. 32.9/46.8/20.3 (P = 0.93) or allele frequencies (type 1: M 0.56 vs. 0.55 (P = 0.795); type 2; M 0.56 vs. 0.56 (P = 0.86)) was found, between diabetic patients with or without DN, (ii) no difference was found between normotensive and hypertensive diabetic patients.. The data argue against a role of the angiotensinogen gene M235T polymorphism in the manifestation of diabetic nephropathy or hypertension in diabetic patients.

Topics: Adult; Age of Onset; Aged; Alleles; Angiotensinogen; Base Sequence; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Primers; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic

The influence of altered dietary sodium on angiotensinogen and renin gene expression was examined in young normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Artificial rearing was used to increase or decrease dietary sodium intake during the preweanling period. In normally reared control animals, renal renin and liver angiotensinogen mRNA decreased between 6 and 30 postnatal days of age. In contrast, in the central nervous system, angiotensinogen mRNA increased between 6 and 30 days of age, and renin mRNA remained stable. Dietary sodium manipulation between postnatal days (PD) 6 and 18 significantly influenced renal renin gene expression, with low-sodium diet increasing renin mRNA on PD12 and PD18 and high-sodium diet decreasing renin mRNA on PD18. Liver angiotensinogen mRNA decreased for animals on either diet on PD12 and PD18. Brain angiotensinogen and renin mRNA were not affected by dietary sodium levels. There were no strain-related differences in the response to high and low dietary sodium. These results demonstrate that 1) the peripheral and central renin-angiotensin systems do not have a common ontogenetic pattern of development, 2) they are independently regulated in response to dietary sodium variations, and 3) young WKY and SHR share very similar ontogenetic patterns of angiotensinogen and renin gene expression.

Topics: Angiotensinogen; Animals; Animals, Suckling; Body Weight; Brain; Female; Gene Expression; Hypertension; Kidney; Liver; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Renin; RNA, Messenger; Sodium, Dietary

To investigate whether the polymorphisms in the angiotensin-converting enzyme and angiotensinogen genes are associated with hypertension, we carried out a case-control study of 508 hypertensive and 523 control subjects randomly selected from the Social Insurance Institution register. The cohorts were well characterized and matched for age and sex. The insertion/ deletion polymorphism of the angiotensin-converting enzyme gene and the methionine-->threonine variant at position 235 of the angiotensinogen gene were determined by the polymerase chain reaction technique. The allele frequencies and genotype distributions of both polymorphisms were similar in hypertensive and control subjects. Systolic and diastolic pressures adjusted for age, body mass index, and alcohol consumption did not differ significantly between the different genotypes of the angiotensin-converting enzyme and angiotensinogen genes. The variation at the angiotensinogen and angiotensin-converting enzyme genes did not have any statistically significant synergistic effect on blood pressure levels. In conclusion, the polymorphisms in the reninangiotensin cascade genes do not confer a significantly increased risk for the development of hypertension in this middle-aged, population-based cohort.

Topics: Adult; Angiotensinogen; Blood Pressure; Cohort Studies; Female; Finland; Genes, ras; Genetic Variation; Genetics, Population; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Prevalence; Random Allocation

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Crosses, Genetic; Disease Models, Animal; Female; Humans; Hypertension; Male; Mice; Mice, Transgenic; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Renin

Topics: Adolescent; Adult; Aged; Aldosterone; Angiotensin II; Angiotensinogen; Blood Flow Velocity; Genotype; Humans; Hypertension; Kidney; Middle Aged; Phenotype; Renin; Sodium, Dietary

To determine whether the M235-->T polymorphism (exon 2) of the angiotensinogen gene is associated with hypertension in elderly patients with isolated systolic hypertension [ISH: systolic blood pressure (SBP) > or = 160 mmHg, diastolic blood pressure (DBP) < 90 mmHg) or systolic-diastolic hypertension (SDH: DBP > or = 90 mmHg, SBP > or = 160 mmHg) compared with normotensive controls (SBP < 160 mmHg, DBP < 90 mmHg).. A case-control study in 769 non-institutionalized, elderly (aged > or = 60 years; female:male ratio 0.85) residents of Dubbo, New South Wales.. Individuals were classified as having ISH (n = 171), having SDH (n = 218) and being normotensive controls (n = 366) with age and sex matching. MM, TT and MT genotypes were determined by a nested polymerase chain reaction strategy using DNA extracted from serum. The prediction of ISH or SDH by genotype or allele was examined in a multiple-logistic regression model that controlled for various confounders.. SBP (mean +/- SD, mmHg)/DBP (mean +/- SD, mmHg) was 176 +/- 16/79 +/- 8 in the ISH group, 167 +/- 23/97 +/- 7 in the SDH group and 134 +/- 14/74 +/- 9 in the normotensive control group. The frequencies of M and T alleles in the normal population (0.69 and 0.31, respectively) were altered significantly in the ISH group (0.61 and 0.39, respectively; chi 2 = 6.0, P < 0.02) and the SDH group (0.62 and 0.38, respectively; chi 2 = 6.0, P < 0.02). The presence of the TT genotype predicted both ISH (odds ratio 1.9, 95% confidence interval 1.1-3.3) and SDH (1.7, 1.0-3.0) as did that of the T allele (ISH: 1.3, 1.0-1.7; SDH: 1.3, 1.0-1.7).. The M235-->T polymorphism may be a marker for both forms of hypertension in the elderly. Whether the TT genotype represents a genetic risk factor for the development of hypertension in later life requires confirmation.

Topics: Aged; Angiotensinogen; Case-Control Studies; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Restriction Fragment Length

The factors that initiate chronic renal failure in patients with hypertension, diabetes mellitus, and chronic glomerular disease are largely unknown. The likely genetic contribution to ESRD, particularly in African Americans, suggests that linkage analysis may be useful to evaluate the role of candidate genes in the pathogenesis of chronic renal failure. The renin-angiotensin-aldosterone (RAA) axis has been intensively evaluated for its contribution to cardiovascular disease and nephropathy. This study tested for linkage between candidate genes in the RAA axis and chronic renal failure, using 85 African-American sibling pairs (from 65 families) concordant for ESRD. Angiotensinogen was selected because of the putative link between it and mild to moderate essential hypertension and nephrosclerosis; angiotensin-converting enzyme because of its possible contribution to diabetic nephropathy; and renin, the angiotensin II receptor, and kallikrein because of their roles in hypertension and renal perfusion. These candidate loci did not demonstrate linkage to either diabetic or nondiabetic renal disease in this study's collection of sibling pairs. These results suggest that polymorphisms at these RAA axis loci do not make major contributions to the pathogenesis of renal disease in African Americans.

Topics: Angiotensinogen; Black People; Diabetes Complications; Family; Female; Genetic Linkage; Humans; Hypertension; Kidney Failure, Chronic; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin; Renin-Angiotensin System

The association of the variant in the 5'-regulatory region of angiotensinogen gene with primary hypertension in the Han Nationality in China was studied by applying PCR-SSCP analysis and DNA cycle sequencing. The frequencies of three identified SSCP-patterns (pattern-A, B, C) in 73 hypertensive subjects were compared with those in 74 normal controls. It was found that the number of pattern-C was higher in the study group (5/73) than in the controls (1/74). The results of DNA sequencing showed that the difference of three SSCP-patterns was caused by a nucleotide substitution G-->A at -216 locus in the 5'-upstream region of angiotensinogen gene, and the subjects with pattern-C were homozygous for mutant A-allele (genotype A/A). These results suggest that the identified gene variant may be associated with primary hypertension.

Topics: Aged; Angiotensinogen; Female; Humans; Hypertension; Male; Middle Aged; Pedigree; Point Mutation; Polymorphism, Single-Stranded Conformational; Sequence Analysis, DNA

To study the effect of captopril treatment and its withdrawal on the circulating and tissue peptidyl-dipeptidase A, angiotensinogen (AGT), and angiotensin II (A II), in relation to left ventricular hypertrophy (LVH) and systolic blood pressure (SBP).. SHR male rats were given captopril 100 mg.kg-1.d-1 [SHRcap, number (n) = 43] orally in mixture with milk powder as vehicle from intrautero period of 16 wk of age. Rats were killed at 16 (n = 19) and 40 (n = 24) wk of age, respectively. Male, age-matched untreated SHR and WKY rats served as controls. SBP, left ventricular mass/body weight (LVM/BW) ratio, left ventricular (LV) myocardium and plasma A II concentration, aortic and serum peptidyl-dipeptidase A activity, AGT mRNA level in kidney and liver, renal renin mRNA level were determined.. Captopril treatment decreased SBP and reduced LVM/BW at 16 and 40 wk of age, and persistently inhibited LV myocardium A II, aortic peptidyl-dipeptidase A activity, and AGT gene expression in kidney even after the treatment was removed. Nevertheless, no changes were found in plasma A II concentration, serum peptidyl-dipeptidase A activity, and AGT mRNA level in liver by captopril therapy. Renal renin mRNA level was low in SHR and WKY rats, but it was increased by captopril treatment. Tissue renin-angiotensin system (RAS) such as AGT mRNA in kidney, aortic peptidyl-dipeptidase A activity, and LV myocardium A II, rather than circulating RAS (AGT mRNA in liver, renin mRNA in kidney, serum peptidyl-dipeptidase A activity and plasma A II), were persistently inhibited by early captopril treatment, even after the withdrawal of the treatment.. The long-term inhibition of tissue RAS is one of the mechanisms of the persistent hypotensive effect of captopril treatment.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Captopril; Hypertension; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger

A higher frequency of a variant of the angiotensinogen gene characterized by a transition in exon 2 causing a replacement of methionine by threonine (M235T) has recently been found in hypertensive individuals, but not all authors were able to confirm this observation. We examined (i) 219 patients with primary hypertension, (ii) 92 normotensive controls (spouses), and (iii) a sample of the general population (blood donors, n = 139). Analysis of genomic DNA was performed by PCR amplification and alleles were separated on agarose gels. In the general population and in normotensive spouses the respective frequencies of the T and M alleles were: general population: M = 0.6, T = 0.4; normotensive spouses: M = 0.59, T = 0.41. A significantly higher frequency of the 235T allele was found in hypertensive individuals with a family history of hypertension and an onset of hypertension before 50 years of age (spouses: 0.41 versus HT with age of onset < or = 50 years and family history of HT: 0.56; P = 0.01 by chi 2). In conclusion, the present study confirms the observation of a higher frequency of the 235T allele of the angiotensinogen gene in hypertension and identifies individuals with family history and early onset of hypertension as individuals at risk.

Topics: Adolescent; Adult; Age of Onset; Aged; Alleles; Angiotensinogen; Base Sequence; Genotype; Humans; Hypertension; Medical Records; Middle Aged; Molecular Probes; Molecular Sequence Data; Polymorphism, Genetic

The renin-angiotensin system plays an important role in blood pressure regulation. Angiotensinogen, which is mainly produced in the liver, is a unique component of the renin-angiotensin system, because angiotensinogen is only known as a substrate for angiotensin I generation. It is unclear whether circulating angiotensinogen is a rate-limiting step in blood pressure regulation. Recent findings of genetic studies and analyses suggest that the angiotensinogen gene may be a candidate as a determinant of hypertension. To test the hypothesis that angiotensinogen may modulate blood pressure, we transfected antisense oligonucleotides against rat angiotensinogen into the rat liver via the portal vein using liposomes that contain viral agglutinins to promote fusion with target cells, a technique that has been reported to be highly efficient. Transfection of antisense oligonucleotides resulted in a transient decrease in plasma angiotensinogen levels in spontaneously hypertensive rats from day 1 to day 7 after the injection, consistent with the reduction of hepatic angiotensinogen mRNA. Plasma angiotensin II concentration was also decreased in rats transfected with antisense oligonucleotides. Moreover, a transient decrease in blood pressure from day 1 to day 4 was observed, whereas transfection of sense and scrambled oligonucleotides did not result in any changes in plasma angiotensinogen level, blood pressure, or angiotensinogen mRNA level. Overall, our results demonstrate that transfection of antisense oligonucleotides against rat angiotensinogen resulted in a transient decrease in the high blood pressure of spontaneously hypertensive rats, accompanied by a decrease in angiotensinogen and angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cells, Cultured; DNA, Complementary; Genetic Therapy; Hypertension; Liver; Male; Oligonucleotides, Antisense; Parainfluenza Virus 1, Human; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Wistar; RNA; Time Factors; Transfection

Angiotensinogen gene belongs to the genes designated as hypertension candidate genes. These genes might participate in development of hypertension. The aim of this work was to establish frequency of the mutant allele M235T on angiotensinogen gene in Slovak population and compare this frequency with that obtained from the group of hypertensive patients. We tested DNA from 120 healthy individuals and 20 hypertensive patients. By polymerase chain reaction followed by restriction analysis we determined frequency of mutant allele M235T in healthy population as well as in the group of hypertensive patients. We have found that frequency of the mutant allele in Slovak population was 0.33, while among hypertensive patients 0.45. Percentage of heterozygosity for M235T allele was 44.5%. Frequency of this mutant allele was significantly higher among women compared to men (0.38 vs. 0.27). Increased frequency of M235T allele among hypertensive patients compared to healthy population confirm that M235T mutation is bound to increased blood pressure. This quick and noninvasive method should help in the future to determine the possible risk of hypertension development. (Tab. 1, Fig. 2, Ref. 9.)

Topics: Adult; Alleles; Angiotensinogen; Disease Susceptibility; DNA; Female; Genetic Markers; Humans; Hypertension; Male; Middle Aged; Mutation; Polymerase Chain Reaction

To investigate the gene frequency of the T235 allele and its relationship with hypertension in two Japanese populations.. T235 was investigated by restriction fragment length polymorphism using the polymerase chain reaction technique in 213 Japanese males aged 40-59 years, who were randomly selected from participants in the Jichi Medical School Cohort Study (Awaji-Hokudan population, n = 157; Niigata-Yamato population, n = 56).. The gene frequency of the T235 allele in the two populations was very similar (Awaji-Hokudan 0.65, Niigata-Yamato 0.62; mean 0.64). The T235 frequency was 0.60 in normotensive males, approximately 1.2- to 1.7-fold that in Caucasians. Hypertension, in particular that associated with a positive family history of hypertension, was more common in individuals homozygous for the T235 allele. The levels of total cholesterol, blood glucose and fibrinogen showed a weak and non-significant relationship with the angiotensinogen genotype.. The T235 angiotensinogen allele was more common in Japanese than in Caucasians, and was a predisposing factor for hypertension.

Topics: Adult; Alleles; Angiotensinogen; Base Sequence; Genotype; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Mutation; Risk Factors

There is considerable evidence from clinical and experimental studies that blood pressure is lowered by converting enzyme inhibitors (CEIs) irrespective of whether the plasma renin-angiotensin system (RAS) is stimulated. New insights into the molecular biology of the RAS--in particular, the gene expression of renin and angiotensinogen in various tissues--support the view that the antihypertensive properties of CEIs may be mediated, at least in part, by interaction with tissue RAS. To investigate this possibility further, stroke-prone spontaneously hypertensive male rats (SHRSP) were treated orally for 28 days with different CEIs or a peripheral vasodilator to study the effects of the various drug treatments on the gene expression of the RAS in selected tissues. Different effects of different CEIs on tissue gene expression suggest localized action and some degree of organ specificity of the drugs. The experiments involved: (1) untreated controls; and rats treated with either (2) 50 mg/kg of captopril; (3) 10 mg/kg of lisinopril; (4) 10 mg/kg of cilazapril; (5) or 30 mg/kg of the vasodilator hydralazine with 10 rats/group. All of the study drugs reduced systolic blood pressure to normotension. Cardiac hypertrophy and the heart:body weight ratio were significantly decreased only in the CEI-treated animals, and kidney renin mRNA was increased by the CEIs whereas hydralazine had no effect on heart weight or kidney renin mRNA. Plasma renin activity increased in parallel with kidney renin mRNA levels. Liquid hybridization and Northern blotting assays revealed drug-specific regulation of the angiotensinogen mRNA level in the adrenal gland, with cilazapril producing the most marked stimulation of adrenal angiotensinogen gene expression. Both lisinopril and cilazapril suppressed hypothalamic angiotensinogen mRNA. There were no significant changes in angiotensinogen gene expression observed in the kidney or liver with any of the CEIs. In conclusion, these data show that CEIs interact differentially and drug-specifically with tissue RAS, and have class-specific effects on cardiac hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Gene Expression Regulation; Hypertension; Male; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; RNA, Messenger

The components of the renin-angiotensin system have been implicated in the development of primary hypertension in humans and genetically hypertensive rats. In humans a mutation in the angiotensinogen gene and elevated plasma angiotensinogen levels have been linked to primary hypertension. Although we had previously excluded a linkage of blood pressure to the angiotensinogen gene in the stroke-prone spontaneously hypertensive rat (SHRSP), elevated angiotensin II (Ang II) levels in this strain compared with the normotensive reference, the Wistar-Kyoto rat (WKY), prompted us to investigate further into the origins and effects of altered Ang II regulation using a range of physiological, biochemical, molecular, and genetic approaches. Ang II plasma levels determined by radioimmunoassay were confirmed to be significantly elevated in SHRSP compared with WKY. Sequence comparison among the two rat strains revealed a mutation in the coding region of the angiotensinogen gene that results in an isoleucine-to-valine substitution in SHRSP at amino acid position 154 (I154V). We performed a cosegregation analysis in an F2 intercross cohort bred from SHRSP and WKY from the University of Heidelberg (SHRSPHD and WKYHD) to address the following questions: (1) whether this or another mutation of the angiotensinogen gene may be casually related to the observed differential Ang II plasma levels, (2) whether Ang II plasma levels may be correlated with blood pressure or organ hypertrophy, and (3) whether genetic linkage to the renin or angiotensin-converting enzyme (ACE) gene loci (the two classic regulatory enzymes of the renin-angiotensin system) may provide an explanation for elevated Ang II plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alleles; Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Base Sequence; Female; Genetic Linkage; Hypertension; Male; Molecular Sequence Data; Point Mutation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium, Dietary

The renin-angiotensin system regulates blood pressure and sodium balance. The angiotensinogen gene which encodes the key substrate within this system has been linked to essential hypertension in White Europeans. It has been suggested that people of West African ancestry may have a different genetic basis for hypertension. In this study we have tested whether there is linkage of the angiotensinogen gene to essential hypertension in African Caribbeans from St. Vincent and the Grenadines. DNA from 63 affected sibling pairs with hypertension was tested for linkage by analyzing whether there was excess allele sharing among siblings genotyped using an angiotensinogen dinucleotide repeat sequence. There was significant support for linkage (T = 3.07, P = 0.001) and association of this locus to hypertension (chi 2 = 50.2, 12 degrees of freedom, P << 0.001). A DNA polymorphism which alters methionine to threonine at position 235 (M235T) within the angiotensinogen peptide has been associated previously with hypertension. However, we found no association of this variant with hypertension in this study. These findings provide support for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and suggest some similarities in the genetic basis of essential hypertension in populations of different ethnicity.

Topics: Adult; Africa; Aged; Alcohol Drinking; Alleles; Angiotensinogen; Black People; Blood Glucose; Body Mass Index; Female; Genetic Linkage; Humans; Hypertension; Male; Middle Aged; Nuclear Family; Oligonucleotides; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid; Risk Factors; West Indies

A variant of the angiotensinogen gene, M235T, has been associated with essential hypertension in selected subjects from Paris, France and Salt Lake City, Utah. In the present report, we studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals from Rochester, Minnesota. We determined whether there was a relationship between the M235T polymorphism of the angiotensinogen gene and the occurrence of essential hypertension using two methods. First, a contingency chi-square analysis was carried out to test for an association between the M235T polymorphism and hypertension status. Second, multivariable conditional logistic regression was used to determine whether variation at the M235T polymorphism was a significant predictor of the probability of having essential hypertension. We detected no statistically significant association between the M235T polymorphism and the occurrence of essential hypertension. In particular, the association was not significant in either gender or in a subset of severely hypertensive subjects requiring two or more anti-hypertensive medications. Furthermore, variation in the number of M235T alleles did not make a significant contribution to predicting the probability of having essential hypertension, either alone or in conjunction with other predictor variables. These results suggest that the contribution of variation in the angiotensinogen gene to the occurrence of essential hypertension is less than initially suspected, or may not be constant across populations.

Topics: Aged; Alleles; Angiotensinogen; Antiporters; Apolipoprotein C-II; Apolipoproteins C; Blood Pressure; Body Weight; Case-Control Studies; Chi-Square Distribution; Cholesterol; Female; Genetic Variation; Humans; Hypertension; Male; Middle Aged; Minnesota; Polymorphism, Genetic; Regression Analysis; Triglycerides

Topics: Adult; Angiotensin II; Angiotensinogen; Animals; Birth Weight; Cardiovascular Diseases; Cephalometry; Eclampsia; Embryonic and Fetal Development; Female; Humans; Hypertension; Infant, Newborn; Pregnancy; Pregnancy Complications, Cardiovascular

Variants of the human angiotensinogen gene have been linked in some studies to increased circulating angiotensinogen levels and essential hypertension. To test for direct causality between genotypes at the angiotensinogen locus and blood pressures, we have studied mice carrying zero, one, two, three, or four functional copies of the murine wild-type angiotensinogen gene (Agt) at its normal chromosomal location. Plasma angiotensinogen levels increase progressively, although not linearly, from zero in the zero-copy animals to 145% of normal in the four-copy animals. Mice of all genotypes are normal at birth, but most zero-copy animals die before weaning. The kidneys of the zero-copy animals show pathological changes as adults, but the kidneys are normal in the other genotypes. One adult zero-copy male tested was fertile. The blood pressures of the one-copy through four-copy animals show significant and almost linear increases of approximately 8 mmHg per gene copy despite their normal compensatory mechanisms being intact. These results establish a direct causal relationship between Agt genotypes and blood pressures.

Topics: Aging; Angiotensinogen; Animals; Animals, Newborn; Base Sequence; Blood Pressure; DNA Primers; Female; Genetic Variation; Genotype; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Multigene Family; Polymerase Chain Reaction; Renal Circulation; Renin; Restriction Mapping

Data concerning the effect of angiotensin II (Ang II) on plasma angiotensinogen levels are conflicting. Although Ang II is reported to stimulate the biosynthesis of angiotensinogen, plasma angiotensinogen is often depleted by renin when the level of renin, and therefore Ang II, increases. In the present study we used the Ang II subtype 1 (AT1) receptor antagonist losartan to investigate whether rising plasma Ang II levels stimulate angiotensinogen production to counteract the falling plasma angiotensinogen levels caused by increasing renin activity in plasma.. Angiotensinogen was measured in plasma from two previously reported studies in which 6-week-old stroke-prone spontaneously hypertensive rats (SHRSP) or Dahl salt-sensitive (Dahl-S) rats were fed high-salt diets (4 and 8% sodium chloride, respectively) for 10-12 weeks with or without losartan.. As reported previously, plasma renin was suppressed during the first 4 weeks of the high-salt diet but then paradoxically increased in both strains. When plasma renin increased, plasma angiotensinogen levels fell to 45 and 62% of the baseline value. The plasma renin concentration was negatively correlated with plasma angiotensinogen both in SHRSP and in Dahl-S rats (r = -0.76, P < 0.001 and r = -0.60, P < 0.001, respectively). In Dahl-S rats losartan treatment was associated with lower levels of plasma angiotensinogen but caused greater increases in plasma renin. When differences in renin were taken into account, plasma angiotensinogen levels were not different in losartan-treated and untreated Dahl-S rats. Similarly to Dahl-S rats, plasma angiotensinogen fell in SHRSP when renin increased, but SHRSP had higher plasma angiotensinogen levels during losartan treatment because plasma renin concentration was lower.. The present study shows, in two strains of hypertensive rat, that an increase in plasma renin levels is associated with a fall in plasma angiotensinogen levels. Concurrent treatment with an Ang II AT1 receptor antagonist does not augment this fall, except to the extent that renin rises further. The results provide no evidence for a significant tonic stimulatory effect of Ang II on plasma angiotensinogen levels.

Topics: Administration, Oral; Angiotensin II; Angiotensinogen; Animals; Biphenyl Compounds; Diet; Hypertension; Imidazoles; Losartan; Male; Rats; Rats, Inbred SHR; Renin; Sodium Chloride, Dietary; Tetrazoles

Allelic variants at the human angiotensinogen locus have recently been reported to increase susceptibility to the development of essential hypertension. In this study we analyzed the role played by angiotensinogen in the elevated blood pressure of the spontaneously hypertensive rat (SHR). The SHR angiotensinogen locus (on chromosome 19) cosegregated with a significant (P = .003) and specific increase in pulse pressure in F2 rats derived from a cross of the SHR with the normotensive Wistar-Kyoto rat (WKY), accounting for 20% of the genetic (10% of total) variance in this phenotype. To identify potential mechanisms underlying the effect of the locus, we further examined angiotensinogen structure and expression in the two strains. Sequence analysis of the respective coding regions revealed no differences in the primary structure of angiotensinogen between the strains. Likewise, plasma angiotensinogen level did not differ in adult rats of the two strains. However, gene expression studies showed tissue-specific, age-related differences in angiotensinogen mRNA levels between SHR and WKY, particularly in the aorta. The findings suggest that pulse pressure, which significantly influences cardiovascular risk, has independent genetic determinants. They further suggest that the effect of the angiotensinogen locus on this phenotype in the SHR may be mediated through a tissue-specific abnormality of angiotensinogen gene expression.

Topics: Angiotensinogen; Animals; Base Sequence; Chromosome Mapping; Female; Genotype; Hypertension; Male; Molecular Sequence Data; Polymorphism, Restriction Fragment Length; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA, Messenger

The angiotensinogen (AGT) gene has been implicated as a candidate gene of high blood pressure. However, because the variants of the AGT gene are point mutations, it is difficult to detect them in large scale population studies. The aims of this study were to develop a rapid screening method for the point mutations and, using this method, to determine the possible role of the AGT gene variant in high blood pressure in the Japanese population.. A rapid screening method for the point mutations by means of primer-specified restriction map modification is described here. Using this method, the distribution of two variants of the AGT gene, M235T and T174M, was determined in 80 patients with essential hypertension (EHT) and 100 normotensive controls (control).. The hypertensive group showed a significantly (P < 0.05) higher frequency for the T174M variant but the same frequency for the M235T variant.. These data provide evidence in favour of an association between hypertension and a genetic variant of AGT in human EHT, and a marked ethnic difference in the AGT gene.

Topics: Adult; Alleles; Angiotensinogen; Base Sequence; Female; Humans; Hypertension; Japan; Male; Middle Aged; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; Prevalence

Phosphorothioated antisense oligodeoxynucleotide (ASODN) targeted to angiotensinogen mRNA was administered intracerebroventricularly in spontaneously hypertensive rats to test whether angiotensinogen reduction would lower their hypertensive blood pressures. The ASODN lowers hypertensive blood pressures to normotensive levels in spontaneously hypertensive rats; sense oligodeoxynucleotide had no effect. Administration of phosphorothioated ASODN produced a prolonged duration of lowered blood pressure. Injections of ASODN at the same dose that decreased hypertension when administered centrally did not result in blood pressure decreases when administered intra-arterially. Furthermore, angiotensinogen production was decreased in the brain stem and significantly decreased in the hypothalamus of the ASODN-treated rats (P < .05), supporting the concept of centrally mediated regulation of hypertension by an overactive brain angiotensin system. To determine the distribution of centrally administered oligodeoxynucleotides, fluorescein isothiocyanate-conjugated oligodeoxynucleotides were injected directly into the lateral ventricles. One hour later, oligodeoxynucleotides were distributed throughout the lateral and third ventricles, with tissue and cellular uptake observed in discrete cells at the injection site. This indicates that the oligodeoxynucleotides are taken up rapidly by brain cells and that they permeate the areas surrounding brain nuclei involved in central blood pressure regulation and volume homeostasis. The results confirm and extend our previous study with phosphodiester ASODN and show that phosphorothioation modification increases the duration of the response and is taken up in vivo. We conclude that with modification, ASODN inhibition of angiotensinogen mRNA translation can be used for a prolonged, profound decrease in mean arterial pressure in the spontaneously hypertensive rat through a central mechanism.

Topics: Angiotensinogen; Animals; Antisense Elements (Genetics); Base Sequence; Blood Pressure; Brain; Fluorescein-5-isothiocyanate; Hypertension; Injections, Intraventricular; Male; Molecular Sequence Data; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; RNA, Messenger

The T235 allele of the angiotensinogen gene (AGT) has been associated with hypertension. Blood pressure increases faster over time in black children than in white children, and in adults hypertension is more prevalent in blacks. We sought evidence for a role for angiotensinogen to contribute to racial differences in blood pressure in a study of 148 white and 62 black normotensive children (mean age, 14.8 yr). The frequency of the T235 allele was 0.81 in blacks and 0.42 in whites (chi 2 = 77.3, P = 0.0001). The mean angiotensinogen level was 19% higher in blacks than in whites (P = 0.0001 for males, P = 0.004 for females). Genotype was positively related to serum angiotensinogen in white children (P = 0.0001 for males, P = 0.004 for females), but a similar relationship was absent in blacks where the frequency of M235 may have been too low to discern an association. Longitudinal blood pressure (measured twice yearly) adjusted for body mass index showed a marginally significant relationship to the angiotensinogen level (P = 0.07). An independent relationship of serum angiotensinogen with body mass index (P = 0.0001) and race (P = 0.0003) was also observed. In summary, T235 was more frequent, and the level of angiotensinogen was higher in blacks than in whites. Such a racial difference in the renin-angiotensin system may contribute to the disparity in blood pressure levels of white and black young people.

Topics: Adolescent; Adult; Aldosterone; Alleles; Angiotensinogen; Base Sequence; Black People; Blood Pressure Determination; Child; Female; Gene Frequency; Genetic Variation; Humans; Hypertension; Indiana; Longitudinal Studies; Male; Molecular Sequence Data; Renin; White People

Genetic influences in cerebrovascular disease (CVD) may act either independently or by predisposing to, or modulating, the effect of risk factors such as hypertension. Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction are important in CVD. The angiotensinogen gene has recently been linked with essential hypertension in affected sibships and a particular polymorphism in exon 2 of the angiotensinogen gene, a threonine to methionine substitution at position 235 (M235T), has been associated with pre-eclampsia and hypertension. In this study we examined the relation of M235T polymorphism to cerebrovascular disease and carotid atheroma in 100 consecutive Caucasian patients with internal carotid artery territory ischaemia (TIA or stroke), presenting to a carotid ultrasound service. Forty five age-matched controls (mostly patients' spouses) were also studied. Hypertension was defined as current treatment with anti-hypertensive agents, or SBP > 160 mm Hg or DBP > 95 mm Hg. Twelve of 100 cases (12%) and eight of 45 controls (12%) were homozygous for the T235 allele. T:M allele ratios were 0.34:0.66 in cases and 0.34:0.66 in controls. There was no relation between the polymorphism and either internal carotid stenosis or common carotid artery intima-media thickness. In the cases, mean percentage internal carotid artery stenosis was TT 18.3 (SD 18.7)%, MT 38.0 (27.1)% and MM 36.8 (30.2)%. Mean intima-media thickness was TT 0.87 (0.18) mm, MT 0.95 (0.34) mm and MM 0.88 (0.23) mm. There was no relation between the polymorphism and hypertension (TT 11 of 100 cases, six of 45 controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Alleles; Analysis of Variance; Angiotensinogen; Arteriosclerosis; Carotid Stenosis; Case-Control Studies; Cerebrovascular Disorders; Female; Homozygote; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Threonine; Ultrasonography, Doppler, Color

When spontaneously hypertensive rats (SHR) treated at a young age with an inhibitor of angiotensin-converting enzyme (ACE) are withdrawn from treatment, their blood pressure (BP) remains below that of untreated rats. We examined the effects of ACE inhibitor treatment and its withdrawal on angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II) and angiotensin I (Ang I) in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats. Rats were administered either vehicle or perindopril (3 mg/kg/day) from 6 to 10 weeks, from 6 to 20 weeks, and from 6 to 10 weeks, followed by perindopril withdrawal from 10 to 20 weeks. Angiotensin peptides and plasma levels of renin, angiotensinogen, ACE, and aldosterone were measured at 10 and 20 weeks of age. Perindopril reduced BP of both SHR and Donryu rats, although only SHR showed a reduction of BP of 19 mm Hg after perindopril withdrawal, associated with a reduction of 5% in heart weight/body weight ratio. Perindopril reduced the angiotensin II/angiotensin I ratio in all tissues by > 50%, with strain- and tissue-specific differences in the effects of perindopril on the levels of individual angiotensin peptides. None of the changes in Ang II levels persisted after perindopril withdrawal. In contrast to those of Donryu rats, plasma angiotensinogen levels of perindopril-withdrawn SHR were 14% lower than those of vehicle-treated SHR (p = 0.0356). Although the lower BP of perindopril-withdrawn SHR was not associated with an alteration in Ang II levels, the suppressed plasma angiotensinogen levels may have contributed to the lower BP of these rats. Alternatively, another action of perindopril, such as a change in cardiovascular structure, may have been responsible for the reduced BP of perindopril-withdrawn SHR.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Hypertension; Indoles; Male; Peptide Fragments; Perindopril; Radioimmunoassay; Rats; Rats, Inbred SHR; Renin; Tissue Distribution

1. Tsukuba hypertensive mice (THM) carry both human renin and angiotensinogen genes, and develop hypertension. The animal has high levels of renin activity and angiotensin II concentration in the plasma. 2. Urinary excretion in THM was greater than in the control animal, non-transgenic C57BL/6j. THM showed a greater amount of daily water intake. The osmolality of 24 h urine was lower than that of the control animal. 3. When water was deprived for 12 h and then loaded with 0.25 mL/10 g bodyweight, the osmolality of urine at the first 0-3 h period was the same in THM and control, but significantly lower in THM at the following 3-6 h period, indicating that the urine concentrating activity is insufficient in THM compared with the control animal. 4. Urinary excretion of vasopressin was significantly higher in THM. Plasma aldosterone concentration and urinary excretion of aldosterone were also higher in THM. Plasma potassium level was significantly low. 5. The mechanism underlying the pathophysiology of polyuria is not totally explained; however, hypokalaemia, which was probably the result of hyperaldosteronism, may be at least partially involved, since hypokalaemia is considered to be a factor hampering the action of vasopressin for concentration of urine at the site of the collecting duct of the kidney.

Topics: Aldosterone; Angiotensinogen; Animals; Electrolytes; Humans; Hyperaldosteronism; Hypertension; Kidney Concentrating Ability; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Polyuria; Rats; Renin; Vasopressins

To investigate the effects of renal transplantation on the plasma and local kidney renin-angiotensin systems of the recipients the left kidneys of 13 adult male Wistar-Kyoto rats (WKY) and 13 stroke-prone spontaneously hypertensive rats (SHRSP) were transplanted to bilaterally nephrectomized (WKYxSHRSP)-F1 hybrids. Nine unilaterally nephrectomized WKY and nine SHRSP served as controls. Four weeks after surgery recipients of an SHRSP kidney but not recipients of a WKY kidney had significant post-transplantation hypertension. Plasma renin activity (PRA) was higher in SHRSP than in WKY. Transplanted rats had lower PRAs than nontransplanted controls. Plasma ACE activity was lowest in SHRSP, intermediate in transplanted F1 hybrids and highest in WKY. Plasma Ang I and Ang II concentrations closely paralleled each other. They were not significantly different between WKY and SHRSP and lower in transplanted than in nontransplanted rats. ACE and renin mRNA were lower in transplanted than in nontransplanted kidneys. Glomerular angiotensin II receptor density was higher in transplanted than in nontransplanted kidneys with no significant differences between strains. We conclude that renal transplantation has profound long-term effects on the recipients' plasma and local kidney renin-angiotensin systems. These do not appear to be involved in the pathogenesis of post-transplantation hypertension in recipients of an SHRSP kidney, but may reflect a role for the intrarenal renin-angiotensin system in long-term renal adaptation and repair processes after transplantation.

Topics: Acetylcholinesterase; Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Disease Models, Animal; Hybridization, Genetic; Hypertension; Kidney; Kidney Transplantation; Male; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System; RNA, Messenger

There are several ways of experimentally studying the influence of candidate genes on hypertension. The approach proposed here is antisense inhibition with antisense oligodeoxynucleotides (AS-ODNs) constructed to the 5' region of known sequences of angiotensinogen mRNA and angiotensin II type-1 receptor mRNA. The AS-ODNs were applied in vivo and in vitro. In vivo, direct injection of 50 micrograms of AS-ODN into the lateral ventricles of SHR reduced hypertension significantly (P < 0.01). There was no effect of AS-ODN i.c.v. in normotensive WKY rats. The phosphorothiated AS-ODN to the AT1 receptor mRNA also produced a long-lasting decrease in blood pressure in SHR (7 days). After AS-ODN treatment AT1 receptors were reduced in the PVN and anterior third ventricle area and Ang II levels were reduced in the brainstem. The results show the in vivo feasibility of using antisense inhibition of renin-angiotensin mRNA to reduce hypertension.

Topics: Angiotensinogen; Animals; Base Sequence; Blood Pressure; Hypertension; Male; Molecular Sequence Data; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger

The renin-angiotensin system is a major determinant of arterial pressure and volume homeostasis in mammals through the actions of angiotensin II, the proteolytic digestion product of angiotensinogen. Molecular genetic studies in several human populations have revealed genetic linkage between the angiotensinogen gene and both hypertension and increased plasma angiotensinogen. Transgenic mice were generated with a human angiotensinogen genomic clone to develop an animal model to examine tissue- and cell-specific expression of the gene and to determine if overexpression of angiotensinogen results in hypertension. Human angiotensinogen mRNA was expressed in transgenic mouse liver, kidney, heart, adrenal gland, ovary, brain, and white and brown adipose tissue and, in kidney, was exclusively localized to epithelial cells of the proximal convoluted tubules. Plasma levels of human angiotensinogen were approximately 150-fold higher in transgenic mice than that found normally in human plasma. The blood pressure of mice bearing the human angiotensinogen gene was normal but infusion of a single bolus dose of purified human renin resulted in a transient increase in blood pressure of approximately 30 mm Hg within 2 min. These results suggest that abnormalities in the angiotensinogen gene resulting in increased circulating levels of angiotensinogen could potentially contribute in part to the pathogenesis of essential hypertension.

Topics: Angiotensinogen; Animals; Base Sequence; DNA Primers; Humans; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Recombinant Proteins

An association study of the polymorphism of the angiotensinogen gene, consisting of T-->C transition at nucleotide 704 in exon 2, with essential hypertension in the Japanese population was performed by restriction fragment length polymorphism (RFLP). The allele which contained the Tth 111-I restriction site in the presence of C transition was designated 'a' and the allele that lacked restriction site was designated 'A'. The frequency of aa genotype in our normotensive group was higher than the previously reported values in Caucasians. In spite of the high frequency of the aa genotype in Japanese, the aa genotype was significantly more frequent in 108 hypertensives than in 104 normotensive subjects compared with the two other genotypes (P = 0.009). These results suggested that this molecular variant of the angiotensinogen gene may be a preserved inherited predisposition for essential hypertension in various ethnic groups, including Caucasians and Japanese.

Topics: Angiotensinogen; Asian People; Base Sequence; Female; Gene Frequency; Humans; Hypertension; Japan; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length

Two mutations (T174M and M235T) in the angiotensinogen gene have been reported to be associated with hypertension. This study examines the frequency of these mutations among African-American hypertensive patients (n = 109). The allele frequency of the T174M mutation was 4.6% and the frequency of the M235T mutation was 86.7%. The genotypic frequencies agreed with the conditioned Hardy-Weinberg predictions based on allele frequencies. The homozygote wild-type genotype at the T174 site was more frequent than the mutation and occurred at a rate of 91.7%. Conversely, the homozygote for the mutation at the M235 site was more frequent and occurred at a rate of 75.2%. Mutation frequencies for T174M and M235T in this African-American population differ from those previously reported from a white hypertensive population (P = .0058 and P = .0001, respectively). In summary, the representation of the angiotensinogen allele frequencies differ among hypertensive populations.

Topics: Adult; Aged; Alleles; Angiotensinogen; Base Sequence; Black People; Female; Gene Frequency; Genes; Genotype; Humans; Hypertension; Male; Middle Aged; Molecular Probes; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Polymorphism, Genetic

The Hutterite Brethren are a genetic isolate characterized by high indices of relatedness and a communal agrarian lifestyle. We hypothesized that variation of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes would be associated with variation in resting blood pressure in this group. We also hypothesized that the association would depend on the sex of the subjects.. In 741 Hutterites, we measured blood pressure in quadruplicate and analyzed DNA for genotypes of an insertion/deletion (I/D) polymorphism of ACE and of two protein polymorphisms of AGT, namely, M235T and T174M. We tested for association between variation in systolic and diastolic blood pressures and genotypic class. We observed that genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure. We also tested for an interaction between the AGT genotype and sex. We observed that genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure only in men. The AGT codon 174 polymorphism accounted for 3.1% of the total variation in systolic blood pressure in men.. The association of AGT variation with resting blood pressure in men is consistent with the existence of important structural elements within, flanking, or proximal to the AGT gene, whose functional impact might be related to differences in sex.

Topics: Adult; Aged; Alleles; Angiotensinogen; Blood Pressure; Codon; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Sex Factors

We describe angiotensinogen gene (AGT) polymorphic frequencies in different ethnic groups in London, both normotensive and hypertensive. The methodology is a recently described direct PCR technique. Results show that there is a marked difference in T-235 frequency between ethnic groups. However, there was no apparent association of T-235 with hypertension.

Topics: Angiotensinogen; Black People; Case-Control Studies; Cross-Sectional Studies; Gene Frequency; Genotype; Humans; Hypertension; London; Polymerase Chain Reaction; White People

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 +/- 3 mmHg vs control 125 +/- 1 mmHg, P < 0.0001). 3. Mesenteric resistance arteries (200-300 microns) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10(-11)-10(-6) mol/L), angiotensin I (10(-11)-10(-6) mol/L) and angiotensin II (10(-12)-10(-6) mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cyclosporine; Female; Hypertension; In Vitro Techniques; Mesenteric Arteries; Rats; Rats, Wistar; Renin-Angiotensin System; Sensitivity and Specificity; Vascular Resistance; Vasoconstriction

Topics: Angiotensinogen; Genetic Linkage; Humans; Hypertension; Polymorphism, Genetic

Angiotensinogen gene expression is controlled in a tissue- and development-specific manner. Interestingly, the angiotensinogen gene is abundantly expressed in adipose tissues other than the liver, where it is mainly produced. We investigated the molecular mechanism of angiotensinogen gene expression in a 3T3-L1 preadipocyte-adipocyte system. Although angiotensinogen mRNA was barely detectable in preadipocytes, its levels increased significantly during differentiation. As a whole, the pattern of the change in transcriptional activity of the angiotensinogen promoter was similar to that of the angiotensinogen mRNA levels during adipogenic differentiation, indicating that the activation of the angiotensinogen promoter might be involved in the adipogenic differentiation-coupled gene expression. The proximal promoter region, from -96 to +22 of the transcriptional start site, was sufficient to confer adipogenic activation, and the proximal element from -96 to -52 of the transcriptional start site was necessary for this promoter stimulation. DNA-protein binding experiments showed that this proximal element specifically bound to a nuclear factor induced by adipogenic differentiation. These results suggest that the proximal promoter element from -96 to -52 plays a role in adipogenic activation of the angiotensinogen promoter.

Topics: 3T3 Cells; Adipocytes; Angiotensinogen; Animals; DNA; Gene Expression Regulation; Hypertension; Mice; Promoter Regions, Genetic; RNA, Messenger; Transfection

A common molecular variant of angiotensinogen (AGT), the precursor of the potent vasoactive hormone angiotensin II, has been incriminated as a marker for a genetic predisposition to essential hypertension in Caucasians (Jeunemaitre, X., F. Soubrier, Y. V. Kotelevtsev, R. P. Lifton, C. S. Williams, A. Charru, S. C. Hunt, P. N. Hopkins, R. R. Williams, J. M. Lalouel, and P. Corvol. 1992. Cell. 71:169-180). We now show that the same variant, T235, is associated with essential hypertension in Japanese patients. The observation of this association in a distinct, ethnically homogeneous population further substantiates an involvement of angiotensinogen in the pathogenesis of essential hypertension and has physiological, epidemiological, and evolutionary implications.

Topics: Adolescent; Adult; Aged; Alleles; Angiotensinogen; Genotype; Humans; Hypertension; Japan; Middle Aged; Risk Factors

The transgenic rat TGR(mRen-2)27, in which the Ren-2 mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouse Ren-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4 +/- 37.3 ng angiotensin I/mL, n = 4). The reaction of purified mouse Ren-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from 253.4 +/- 66.7 to 225,000 +/- 48,000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 microL of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7 +/- 4.7 and 61.8 +/- 2.7 mmHg, respectively, whereas injection of 200 microL of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Hydrogen-Ion Concentration; Hypertension; Kinetics; Male; Mice; Mice, Inbred DBA; Rats; Rats, Sprague-Dawley; Renin

Experimental analysis of complex quantitative genetic traits, such as essential hypertension, should be greatly facilitated by being able to manipulate the expression of a gene in living animals without altering the nucleotide sequence, chromosomal location, or regulatory elements of the gene. To explore this possibility, we have used targeted gene disruption and duplication to generate mice that are genetically identical [(129 x C57BL6)F1] except for having one, two, or three functional copies of the gene coding for angiotensinogen. The two-copy animals have two normal copies of the angiotensinogen gene; the one-copy and three-copy animals have one normal copy with the other either disrupted or duplicated by gene targeting. The duplicated pair of genes was generated by a special form of gap-repair gene targeting that tandemly duplicates the whole of a gene together with 5' and 3' flanking regions. We find progressively and significantly higher levels of the gene product in the animals having increasing numbers of gene copies: the one-copy animals have steady-state plasma angiotensinogen levels approximately 35% of normal (P < 0.0001), and the three-copy animals have levels approximately 124% of normal (P < 0.004). Detailed information about regulatory sequences is not required for this type of experiment; nor is it necessary to have DNA clones or targeting constructs that cover the whole of the target gene. Varying gene copy numbers by targeting consequently offers a promising approach to quantitative genetics.

Topics: Angiotensinogen; Animals; Base Sequence; DNA Primers; DNA Repair; Female; Gene Expression; Hypertension; Male; Mice; Mice, Knockout; Molecular Sequence Data; Multigene Family; Restriction Mapping

The renin-angiotensin system is a powerful pressor system with a major influence on salt and water homeostasis. Angiotensinogen (also called renin substrate) is a key component of this system; it is cleaved by renin to yield angiotensin I, which is then cleaved by angiotensin-converting enzyme to yield angiotensin II. The observation that plasma angiotensinogen levels correlate with blood pressure and track through families suggests that angiotensinogen may have a role in essential hypertension. We therefore investigated whether there is linkage between the angiotensinogen gene on chromosome 1q42-43 and essential hypertension.. Samples of DNA from 63 white European families in which two or more members had essential hypertension were tested for linkage of the angiotensinogen gene to this disorder. Affected cousins, nephews, nieces, and half-siblings were included when possible. To test for linkage, we used as a marker a dinucleotide-repeat sequence flanking this gene, and we employed the affected-pedigree-member method of linkage analysis. Two molecular variants of the angiotensinogen gene, one encoding threonine instead of methionine at position 235 (M235T) and the other encoding methionine rather than threonine at position 174 (T174M), were also tested for possible association with essential hypertension.. We found significant linkage (t = 5.00, P < 0.001) and association (chi-square = 53.3, P < 0.001) of the angiotensinogen-gene locus to essential hypertension in the 63 multiplex families. This linkage was consistently maintained in the subgroup of subjects with diastolic pressure above 100 mm Hg and in the subgroups classified according to sex. It has been proposed previously that T174M and M235T are associated with essential hypertension. However, we found no association in our population between either polymorphism and this disorder.. This study provides strong and consistent support for the linkage to essential hypertension of regions within or close to the angiotensinogen gene. Precisely how mutations in this region may result in hypertension remains to be determined.

Topics: Aged; Angiotensinogen; Base Sequence; Chromosomes, Human, Pair 1; DNA Primers; Exons; Female; Genetic Linkage; Humans; Hypertension; Male; Methionine; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid; Threonine

Topics: Angiotensinogen; Cardiomegaly; Female; Gene Deletion; Genetic Linkage; Humans; Hypertension; Mutation; Peptidyl-Dipeptidase A

1. A structural alteration within the first intron of the renin gene in spontaneously hypertensive rats was demonstrated to co-segregate with blood pressure in some sets of F2 hybrids or recombinant inbred strains. There is no evidence as to whether restriction fragment length polymorphism of the renin gene is associated with any of the changes in the renin tissue level. For this reason we have determined renal renin activity in spontaneously hypertensive, Wistar-Kyoto and Brown Norway rats as well as in 22 recombinant inbred strains derived from F2 hybrids of spontaneously hypertensive and Brown Norway rats. 2. At the age of 4 months significantly lower renal renin activity was observed in spontaneously hypertensive rats than in both normotensive rat strains, Wistar-Kyoto and Brown Norway. The presence of the spontaneously hypertensive rat allele in recombinant inbred strains was associated with a substantially lower renal renin activity as compared with recombinant inbred strains bearing the Brown Norway rat allele. There was no relationship between renal renin activity and the polymorphism in either the angiotensinogen gene or the angiotensin-converting enzyme gene. 3. There was a borderline correlation between blood pressure and renal renin activity in recombinant inbred strains. Nevertheless, additional comparisons within recombinant inbred strains bearing the spontaneously hypertensive rat allele of the renin gene failed to reveal any significant relationship between blood pressure level and renal renin activity. 4. Our data suggest that the restriction fragment length polymorphism marking the renin gene of the spontaneously hypertensive rat is accompanied by an alteration in the renin-angiotensin system at the renal level.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Genetic Markers; Hypertension; Kidney; Male; Peptidyl-Dipeptidase A; Polymorphism, Restriction Fragment Length; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renin

To determine the role of angiotensinogen and angiotensin II type-1 (AT1) receptor genes in hypertension, spontaneously hypertensive rats (SHR) were injected with synthetic antisense oligodeoxynucleotides (ODNs), intracerebroventricularly (i.c.v). Antisense ODNs were constructed to bases -5 to +13 of angiotensinogen mRNA (18-mer) and to bases +63 to +77 (15-mer) of angiotensin II type-1 receptor mRNA. Hypertension was significantly reduced by the application of 50 micrograms of both antisense ODNs to normotensive levels. The phosphorothioated antisense ODN to the AT1 receptor produced long-lasting (7 days) decreases in blood pressure. After AT1 antisense treatment, AT1 receptors were reduced in the paraventricular nucleus (PVN) and in the anterior third ventricle area (AV3V). Following angiotensinogen antisense treatment, angiotensin II levels were significantly reduced in the brainstem (P < 0.05), indicating arrest of angiotensin II synthesis. The results demonstrate that inhibiting the brain renin-angiotensin system by antisense inhibition of the angiotensinogen and the AT1 receptor genes, lowers high blood pressure in the SHR. The antisense administration to specific genes of the tissue renin-angiotensin system offers the possibility of a new approach to developing antihypertension treatments.

Topics: Angiotensinogen; Animals; Base Sequence; Brain; Hypertension; Male; Molecular Sequence Data; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; RNA, Messenger

To analyze the status of the renin-angiotensin system in hypertensive transplant recipients on cyclosporine, we prospectively explored 21 cardiac (CTR: 52 +/- 8.2 yr) and 12 liver (LTR: 45 +/- 10 yr) transplant recipients on a normal salt diet with 19 normotensive controls in the same age range. Systolic and diastolic blood pressure was measured in the supine and standing positions. Renal function was assessed by serum creatinine values, and 24-hr urinary sodium and potassium excretion were recorded. Plasma renin activity (PRA), active renin, total renin, angiotensinogen, aldosterone, and cortisol plasma levels were simultaneously determined. Results were expressed as mean +/- SD, and between-group differences were compared using variance analysis. Supine blood pressure (+/- SD) was 158 +/- 15/103 +/- 8.4 in CTR and 155 +/- 21.4/102 +/- 11.7 mmHg in LTR. Serum creatinine was higher in CTR (159 +/- 52 mumol/L) than in LTR (117 +/- 24.7, P < 0.05) and values in both groups were above controls (83 +/- 14.1, P < 0.05). Urinary sodium excretion tended to be lower in transplant recipients (59 +/- 42 mmol/L) for CTR and 44 +/- 36.7 in LTR than in healthy controls (117 +/- 24.7 mmol/L). Supine and upright PRA values tended to be higher in hypertensive transplant recipients than in healthy volunteers, although not significantly. Supine active renin was significantly higher in CTR (47 +/- 42 pg/ml) and in LTR (44 +/- 29.8 pg/ml) than in normal subjects (17 +/- 4.8 pg/ml, P < 0.05). Total renin levels in CTR (supine: 716 +/- 357 pg/ml) and in LTR (supine: 647 +/- 365 pg/ml) were 3- to 4-fold higher than in controls (supine: 207 +/- 69 pg/ml) (P < 0.05), as were inactive renin levels (P < 0.01). Active renin was effectively correlated with PRA (P < 0.001) and with total renin (P < 0.001) in the supine and in the upright position. Plasma aldosterone was almost within the normal range in CTR and in LTR, and it did not correlate with PRA values. Plasma angiotensinogen levels were normal in LTR (1032 +/- 226 ng/ml) but were significantly lower in CTR (938 +/- 216 ng/ml, P < 0.05). Cortisol plasma levels were lower in both CTR (7 +/- 4.4 micrograms/L) and LTR (6 +/- 1.9 micrograms/L) than in healthy controls (11 +/- 4 micrograms/L, P < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aldosterone; Analysis of Variance; Angiotensinogen; Blood Pressure; Cyclosporine; Heart Transplantation; Humans; Hydrocortisone; Hypertension; Liver Transplantation; Middle Aged; Prospective Studies; Renin; Renin-Angiotensin System; Sodium; Supine Position

A recent cross-sectional study of HTs in Salt Lake City and Paris has reported a significant association of a T704-->C (Met235-->Thr) variant in exon 2 of the angiotensinogen gene (AGT) with essential hypertension (HT). The present study used a new, direct PCR technique to detect this variant in 92 Caucasians with severe hypertension (HT) and two HT parents and 94 normotensive (NT) controls. Although frequency of the variant in HTs (0.42) was higher than in NTs (0.39), the difference was not significant (chi 2 = 0.24; P = 0.63). Plasma angiotensinogen showed a weak, nonsignificant relationship with AGT genotype in females and no genotypic relationship was apparent for blood pressure. Thus, if the Met235-->Thr variant of AGT is involved in essential HT, then its contribution may be, at best, much weaker in other HT groups.

Topics: Alleles; Amino Acid Sequence; Angiotensinogen; Base Sequence; Blood Pressure; Body Mass Index; Cross-Sectional Studies; DNA; DNA Primers; Female; Genetic Variation; Genotype; Humans; Hypertension; Leukocytes; Male; Methionine; Middle Aged; Molecular Sequence Data; Paris; Polymerase Chain Reaction; Reference Values; Threonine; Utah

Local or tissue renin angiotensin systems are thought to participate in cardiovascular regulation. However, little information is available on the mechanisms by which renin and angiotensinogen synthesis and secretion are regulated in these tissues. In view of the importance of steroid hormones in the regulation of hepatic angiotensinogen, we have examined the effects of dexamethasone, ethinyl estradiol, or dihydrotestosterone on angiotensinogen gene expression in peripheral or cerebral tissues of Wistar Kyoto (WKY) or spontaneously hypertensive rats (SHR). Following a single injection of dexamethasone (7 mg/kg) the concentrations of angiotensinogen mRNA increased in nearly all organs examined. The differences to controls were higher in SHR than in WKY. Dexamethasone in low doses (10 micrograms/kg/day) given for 10 days did not alter angiotensinogen mRNA or blood pressure in control animals, but increased both parameters in the hypertensive strain. The response to a single dose of ethinyl estradiol (3 mg/kg) was not as uniform as that to dexamethasone, and a tendency for a higher sensitivity was found in SHR. High stimulation rates were found in liver and kidneys of both strains. A single dose of dihydrotestosterone (10 mg/kg) did not significantly affect angiotensinogen mRNA in any organ. Only when a high dose of 50 mg/kg was given daily for 20 days, was angiotensinogen mRNA increased in some tissues. These data indicate that glucocorticoids and estrogens participate in the regulation of angiotensinogen gene expression in several extrahepatic tissues. The higher sensitivity to glucocorticoids in SHR may be relevant for the development of hypertension in this strain.

Topics: Angiotensinogen; Animals; Dexamethasone; Dihydrotestosterone; Drug Resistance; Ethinyl Estradiol; Female; Gene Expression Regulation; Hypertension; Kinetics; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; Steroids; Tissue Distribution

Topics: Angiotensinogen; Humans; Hypertension

In order to study the functional role of the renin-angiotensin system in the control of blood pressure, projects were initiated using transgenic mice carrying either the human renin gene or the human angiotensinogen gene. To extend the usefulness of the transgenic model system of hypertension research, a two-tiered strategy for generation of transgenic mice with high blood pressure has been developed. This unique system allows the establishment of transgenic lines with a strict species specificity of the renin-angiotensinogen reaction exhibited by transgene products that are regulated in a tissue specific manner. In this report, the strategy concerning the "two-tiered method" is presented and evidence is provided the overproduction of angiotensin occurs only in the combined reaction with human renin and human angiotensinogen expressed in transgenic mice.

Topics: Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Hypertension; Kidney; Kinetics; Liver; Mice; Mice, Transgenic; Molecular Sequence Data; Renin; Renin-Angiotensin System; Species Specificity

Pregnancy-induced hypertension (PIH) is a heterogeneous disorder which complicates 5-7% of all pregnancies and remains a leading cause of maternal, fetal and neonatal morbidity and mortality. Severe preeclampsia is the most distinctive and life-threatening form; a multi-system disorder more common in first pregnancies, it is characterized by high blood pressure and proteinuria. In a series of Caucasian women with pregnancy-induced hypertension, we have observed a significant association of preeclampsia with a molecular variant of angiotensinogen, T235, found previously to be associated with essential hypertension. This finding is corroborated in a sample ascertained in Japan. Together, these observations support a new pathophysiological interpretation of preeclampsia and of its relation to some forms of essential hypertension.

Topics: Angiotensinogen; Asian People; Base Sequence; Female; Genetic Variation; Humans; Hypertension; Molecular Sequence Data; Parity; Polymerase Chain Reaction; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin-Angiotensin System; White People

Topics: Angiotensinogen; Eclampsia; Female; Genotype; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics

Topics: Alleles; Amino Acid Sequence; Angiotensinogen; Base Sequence; DNA; Genetic Variation; Humans; Hypertension; Molecular Sequence Data

Essential hypertension is a common human disease believed to result from the interplay of multiple genetic and environmental determinants. In genetic studies of two large panels of hypertensive sibships from widely separated geographical areas, we obtained evidence of genetic linkage between the angiotensinogen gene (AGT) and hypertension, demonstrated association of AGT molecular variants with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects with different AGT genotypes. The corroboration and replication afforded by these results support the interpretation that molecular variants of AGT constitute inherited predispositions to essential hypertension in humans.

Topics: Adult; Analysis of Variance; Angiotensinogen; Base Sequence; Female; Genetic Linkage; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Paris; Pedigree; Polymorphism, Genetic; Utah

Transgenic mice were generated by injecting the entire rat angiotensinogen gene into the germline of NMRI mice. The resulting transgenic animals were characterized with respect to hemodynamics, parameters of the renin angiotension system, and expression of the transgene. The transgenic line TGM(rAOGEN)123 developed hypertension with a mean arterial blood pressure of 158 mmHg in males and 132 mmHg in females. In contrast, the transgenic line TGM(rAOGEN)92 was not hypertensive. Rat angiotensinogen was detectable only in plasma of animals of line 123. Total plasma angiotensinogen and plasma angiotensin II concentrations were about three times as high as those of negative control mice. In TGM(rAOGEN)123 the transgene was highly expressed in liver and brain. Transcripts were also detected in heart, kidney and testis. In TGM(rAOGEN)92 the brain was the main expressing organ. In situ hybridization revealed an mRNA distribution in the brain of TGM(rAOGEN)123 similar to the one in rat. In TGM(rAOGEN)92 the expression pattern in the brain was aberrant. These data indicate that overexpression of the angiotensinogen gene in liver and brain leads to the development of hypertension in transgenic mice. The TGM(rAOGEN)123 constitutes a high angiotensin II type of hypertension and may provide a new experimental animal model to study the kinetics and function of the renin angiotensin system.

Topics: Angiotensinogen; Animals; Blotting, Southern; Brain; Female; Gene Expression; Hypertension; Kidney; Male; Mice; Mice, Transgenic; Myocardium; Nucleic Acid Hybridization; Rats; RNA, Messenger; Testis; Transcription, Genetic

Our previous studies demonstrated that the sexually dimorphic pattern of hypertension in the spontaneously hypertensive rat is androgen dependent. Gonadectomy retards the development of hypertension in young males, but not in females, and administration of testosterone propionate to gonadectomized spontaneously hypertensive rats of both sexes confers a male pattern of blood pressure development. The current study tested the hypothesis that renal and hepatic renin and angiotensinogen gene expression are also androgen dependent in the spontaneously hypertensive rat. Male and female spontaneously hypertensive rats underwent gonadectomy or a sham operation at 4 weeks of age. Subgroups of gonadectomized rats of both sexes were implanted with a 15-mm or 30-mm Silastic capsule filled with testosterone at the same time the gonadectomy was performed; a third group received an empty Silastic capsule. Northern and slot blot analyses were used to characterize and quantitate renin and angiotensinogen messenger RNA (mRNA) in the kidney and liver 18 weeks after the gonadectomy. Blood pressure, plasma renin activity, and hepatic angiotensinogen mRNA levels were higher in intact males than in females. Orchidectomy retarded the development of hypertension and lowered plasma renin and renal and hepatic angiotensinogen mRNA levels, and testosterone replacement restored the male pattern of hypertension and plasma renin and increased renal and hepatic angiotensinogen mRNA. Ovariectomy did not alter blood pressure or plasma renin but did lower renal renin and renal and hepatic angiotensinogen mRNA; testosterone increased blood pressure, plasma renin, renal renin and angiotensinogen mRNA, and hepatic angiotensinogen mRNA levels in ovariectomized females.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensinogen; Animals; Base Sequence; Body Weight; Female; Gene Expression Regulation; Hypertension; Kidney; Liver; Male; Molecular Sequence Data; Orchiectomy; Ovariectomy; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Sex Characteristics; Testosterone

Increasing evidence suggests an association between hypertension and abnormalities of glucose metabolism. Since components of the renin-angiotensin system exist in a variety of tissues consistent with paracrine actions of the peptide, we sought to determine whether the pancreas contains a local angiotensin system. We report the presence of angiotensinogen messenger (m) RNA, angiotensinogen protein, angiotensin II and high-affinity binding sites for angiotensin II in the canine pancreas. These novel findings establish a foundation for future studies to evaluate whether angiotensin acts as a paracrine regulator of endocrine and/or exocrine functions of the pancreas.

Topics: Angiotensin II; Angiotensinogen; Angiotensins; Animals; Autoradiography; Binding Sites; Dogs; Glucose; Hypertension; Male; Pancreas; RNA, Messenger

Angiotensin II was reported to play a key role in ovulation in rats and it seems also to be involved in the regulation of LH release. Thus, we studied the effect of chronic ACE inhibition on the menstrual cycle, measuring daily plasma estradiol, progesterone, LH and FSH, and renin and prorenin before and during the third month of treatment with enalapril (10 mg b.i.d.) in 10 mild essential hypertensive women. Blood pressure was normalized by treatment. The cyclical changes of steroids and gonadotrophins were unaffected in their temporal relationships and in the magnitude of their variation during the experimental cycle compared with the basal cycle. A synchronization of plasma prorenin with the other hormones was seen both before, as previously reported, and during enalapril treatment. Our data show that peripheral blockade of angiotensin I conversion does not affect the pituitary guidance of the ovarian hormonal response or the ovarian prorenin release during the menstrual cycle. Our data are in agreement with the hypothesis that circulating angiotensin II does not play a key role in the human fertility process and that hydrophilic ACE inhibitors can be safely used in the treatment of hypertensive women of reproductive age.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Electrolytes; Estradiol; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Humans; Hypertension; Luteinizing Hormone; Menstrual Cycle; Progesterone; Renin

Topics: Angiotensinogen; Animals; Hypertension; Inflammation; Rats

The brain's renin-angiotensin system in integrally involved in the regulation of blood pressure and fluid/mineral metabolism. Enhanced activity of the angiotensin system in the brain has been implicated as a possible source of the hypertension and the elevated salt appetite of the spontaneously hypertensive rat, as compared with the Wistar-Kyoto rat. This study tested whether these inbred strains of hypertensive and normotensive rats differ in central or peripheral expression of the gene coding for angiotensinogen, the prohormone for the angiotensin peptides. Angiotensinogen messenger RNA was measured in the brain by in situ hybridization and in the liver by Northern blot analysis, using a synthetic oligonucleotide. There was a 28% greater expression of the angiotensinogen gene in the region of the anteroventral hypothalamus, preoptic area, and medial septum of the hypertensive strain. There were no differences between strains in liver angiotensinogen gene expression. These results are consistent with the possibility that enhanced elaboration of the angiotensin prohormone in the brain contributes, in part, to the hypertension or the elevated salt appetite of the spontaneously hypertensive rat.

Topics: Angiotensinogen; Animals; Autoradiography; Base Sequence; Blood Pressure; Blotting, Northern; Brain Chemistry; Gene Expression; Hypertension; Liver; Male; Molecular Sequence Data; Nucleic Acid Hybridization; Oligonucleotide Probes; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger

We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.

Topics: Adult; Angiotensinogen; Female; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Liver Cirrhosis; Male; Middle Aged; Pregnancy; Renin

We have recently shown that the octapeptide angiotensin II is a potent stimulus of protein synthesis and growth in cultured cardiomyocytes. The present study was performed to determine if the renin-angiotensin system was involved in regulating cardiac cell growth in vivo. The pressure-overload cardiac hypertrophy model that develops in abdominal aorta-constricted rats was studied. At 7 and 15 days after abdominal aorta constriction, rats developed significant left ventricular hypertrophy. The increase in left ventricular mass was completely prevented in animals fed the angiotensin-converting enzyme inhibitor, enalapril maleate (0.2 mg/ml) in their drinking water. Cardiac afterload was the same in both groups of animals in that carotid artery pressures were not different in conscious awake aortic-constricted animals receiving and not receiving enalapril. These data suggest a direct growth effect of angiotensin II on the left ventricle and indicate a role for the renin-angiotensin system in the cardiac hypertrophy that develops in response to pressure overload. The presence and chamber localization of angiotensinogen mRNA was determined using Northern hybridization and S1 nuclease mapping analysis. Angiotensinogen mRNA, as determined by dot-blot hybridization analysis, was significantly increased in hypertrophied left ventricles at both 7 and 15 days after the surgery, when compared with sham-operated controls. The activity of the circulating renin-angiotensin system, as indexed by plasma renin activity was increased at 1 day following surgery [6.0 +/- 2.0 ng.ml-1.h-1 angiotensin I (control) vs. 41.8 +/- 10.9 ng.ml-1.h-1 angiotensin I (experimental)], but returned to control values by day 3 postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Aorta; Cardiomegaly; Constriction, Pathologic; Enalapril; Hypertension; Kidney; Male; Myocardium; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; RNA, Messenger; Up-Regulation

Recent epidemiological studies indicate that replacement therapy with oestrogens reduces the cardiovascular risk in postmenopausal women. This protective effect has been ascribed to oestrogen-induced metabolic variations, and notably to the rise of HDL-cholesterol levels observed after oral administration of oestrogens. Recently, long term studies have shown that parenterally administered oestrogens (implants, percutaneous or transdermal administration) have the same effect on blood lipid profile as oral oestrogen over a period of 6 months or more. Factors other than blood lipid changes should be studied in an attempt to elucidate the exact mechanism through which postmenopausal oestrogen administration may reduce the risk of cardiovascular diseases.

Topics: Angiotensinogen; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Estrogen Replacement Therapy; Female; Hemostasis; Humans; Hypertension; Menopause; Triglycerides

When inhibitors of the renin-angiotensin system (RAS) were initially developed, they were believed to act as antihypertensive agents mainly under pathophysiological conditions, in which an elevated plasma RAS contributed to the elevation and maintenance of high blood pressure (BP). However, evidence has accumulated from studies in hypertensive patients, as well as in animals, indicating that BP could be lowered by converting-enzyme inhibitors (CEIs) independently of whether or not the plasma RAS was stimulated. Several other effects had to be considered. It was thus discovered that converting enzyme (CE) is identical with the bradykinin-degrading enzyme, kininase II, and CEIs can therefore potentiate the vasodepressor effects of bradykinin and thereby interact with the prostaglandin system. Actions of CEIs possibly unrelated to inhibition of angiotensin and kininase also need to be considered. The actions of CEIs at the tissue level (brain, heart, blood vessels, kidney, adrenal gland) and their interference with the autonomic nervous system through central and peripheral actions may under certain conditions be more important than their inhibition of the circulating hormonal plasma angiotensin II. Recent clinical and experimental studies and new insights in the molecular biology of the RAS, especially gene expression of renin and angiotensinogen in tissues of the cardiovascular system, support this view. We have found that chronic CE inhibition with substances such as captopril, quinapril and lisinopril specifically affects angiotensinogen mRNA levels in cardiovascular tissues, and has marked effects on left ventricular hypertrophy, possibly through an action on cardiac angiotensin. These findings have consequences not only for the understanding of pharmacokinetics and pharmacodynamics of CEIs but also for their practical therapeutic use.

Topics: Adrenal Glands; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Captopril; Enalapril; Gene Expression Regulation; Heart; Hydralazine; Hypertension; Isoquinolines; Kidney; Lisinopril; Male; Quinapril; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; RNA, Messenger; Tetrahydroisoquinolines

Spontaneously hypertensive Okamoto-strain rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were actively immunized with mouse renin to investigate the effect on blood pressure of blocking the renin-angiotensinogen reaction. Ten male SHR and 10 male WKY rats were immunized with purified mouse submandibular gland renin. Control rats were immunized with bovine serum albumin. Antirenin antibodies were produced by both SHR and WKY rats, but renin-immunized SHR had higher titers of circulating renin antibodies after three injections. The increase in renin antibody in renin-immunized SHR was associated with a significant drop in blood pressure (tail-cuff method) that became similar to that of the WKY control rats after four injections. The blockade by antirenin immunoglobulins of the renin-angiotensinogen reaction also decreased the blood pressure of normotensive rats. Perfusion of renin-immunized rats with mouse submandibular renin (10 micrograms) in vivo caused no increase in blood pressure. Perfusion of renin-immunized, salt-depleted SHR with converting enzyme inhibitor caused no further decrease in blood pressure but significantly decreased blood pressure in salt-depleted control rats. The presence of circulating renin antibodies was associated with low plasma renin activity (0.31 +/- 0.23 ng angiotensin I [Ang I]/ml/hr). Plasma renin activity was unchanged in control animals (13.1 +/- 3.9 ng Ang I/ml/hr in control SHR, 13.9 +/- 3.2 ng Ang I/ml/hr in control WKY rats). Renin antibody-rich serum produced a dose-dependent inhibition of rat renin enzymatic activity in vitro. The chronic blockade of the renin-angiotensinogen reaction in renin-immunized SHR produced an almost-complete disappearance of Ang II (0.8 %/- 7 fmol/ml; control SHR, 30.6 +/- 15.7 fmol/ml) and a 50% reduction in urinary aldosterone. Renin immunization was never associated with a detectable loss of sodium after either 10 or 24 weeks. The glomerular filtration rate was not decreased 10 weeks after renin immunization, whereas blood pressure was significantly decreased, plasma renin activity was blocked, and renal plasma flow was increased. The ratio of left ventricular weight to body weight after 24 weeks was significantly below control levels in renin-immunized WKY rats and SHR. Histological examination of the kidney of renin-immunized SHR showed a chronic autoimmune interstitial nephritis characterized by the presence of immunoglobulins, mononuclear cell infiltration, and fibrosis around

Topics: Aldosterone; Angiotensinogen; Animals; Homeostasis; Hypertension; Immunization; Kidney; Male; Mice; Natriuresis; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System; Urea

The role of the renin-angiotensin system in blood pressure control and in the development of hypertension was investigated by generating transgenic mice carrying the rat renin or angiotensinogen gene or both genes under the control of the mouse metallothionein I promoter. The systolic blood pressure was significantly elevated in transgenic mice carrying both transgenes but was maintained normally in those bearing either of the transgenes. The transgene was effectively and properly transcribed to form the mature mRNA in the transgenic mice. The production of rat renin and angiotensinogen in the transgenic mice carrying the corresponding transgene was also verified by immunoanalyses of these proteins. Furthermore, the specific angiotensin-converting enzyme inhibitor captopril was effective in reducing the elevated blood pressure of the hypertensive transgenic mice. These results indicate that the combined action of the exogenous rat renin and angiotensinogen is responsible and necessary for elevation of blood pressure in the hypertensive transgenic mice.

Topics: Angiotensinogen; Animals; Blood Pressure; Cloning, Molecular; Crosses, Genetic; Female; Genes; Hypertension; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Nucleic Acid Hybridization; Promoter Regions, Genetic; Rats; Renin; RNA, Messenger

The present study analyzed the concentration of renin-like activity and angiotensinogen concentration (AoC) in different brain areas related to cardiovascular control in SHR and Wistar Kyoto (WKY) animals. Male rats of both strains were studied at 8, 16 and 30 weeks of age. The following brain areas were isolated: anterior, medial and posterior hypothalamus, septal area, periaqueductal gray (PG) and the remaining brain stem; nucleus tractus solitarius (NTS) and the remaining medulla oblongata. Plasma renin activity (PRA) and plasma and cerebrospinal fluid (CSF) AoC were determined. Renin-like concentration was higher in SHR than in WKY in the anterior hypothalamus, PG and NTS at different stages of hypertension development. AoC was also higher in some areas of the SHR brain during different periods. PRA, plasma and CSF angiotensinogen concentration showed significant differences between both strain of rats during the development of high blood pressure. Present data support the possibility that the central and peripheral renin-angiotensin system may participate in the maintenance of high blood pressure in the SHR animals.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Brain Chemistry; Hypertension; Male; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System

The cloning of the gene for human renin has permitted remarkable advances to be made in understanding the structure of this aspartyl protease. From computer models and the determination of the actual co-ordinates of expressed recombinant human renin at 3 nm, a considerable amount of information has emerged concerning the molecular mechanism of renin activity, thus permitting the logical design and analysis of renin inhibitors suitable for use in antihypertensive medication. In addition, many of the properties of renin can now be explained in molecular terms, including the species specificity of its reaction with angiotensinogen. From the production of renin inhibitors, the next avenue of research is likely to be the design of drugs that will reduce the activity of the human renin gene and thereby curtail renin production. This may involve a 'new pharmacology' based on transacting factors. Thus cloning of the renin gene has led to elucidation of the tertiary structure of human renin for inhibitor design, and will similarly permit studies of gene-regulatory factors that may be future targets for blockade of the renin system in antihypertensive therapy.

Topics: Amino Acid Sequence; Angiotensin I; Angiotensinogen; Animals; Catalysis; Genes, Regulator; Humans; Hypertension; Mice; Molecular Sequence Data; Protein Conformation; Renin; Species Specificity

A direct radio-immunoassay (RIA) for renin substrate (RS) was compared to the enzymatic (indirect) assay, which measures intact RS only, whereas a direct assay measures both intact RS and des-angiotensin I-RS. In normal subjects, a significant, albeit weak, correlation between the methods was noticed. In hypertensive patients with different levels of plasma renin activity (PRA), RS concentration measured by both assays increased with increasing PRA, and for patients with PRA greater than 10 micrograms AI/l/h, the direct assay gave significantly higher RS values (55%), compared to the enzymatic assay. This indicates consumption of RS by increasing plasma renin and increasing production rate of RS with increasing PRA, of potential importance in the pathogenesis of hypertension. In 11 patients with renovascular hypertension, treatment with the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, resulted in a significant increase in PRA, accompanied by a decrease in RS measured by the enzymatic assay. Lowered plasma RS concentration, by reduction of the velocity of the renin-RS reaction, will distort and invalidate results of PRA determination during treatment with ACE inhibitory compounds. No change in RS measured by direct RIA was noticed, however. The results suggest that ACE inhibition may not have an effect upon RS production and that its effect on plasma RS is limited to a reduction of intact RS measured by the enzymatic assay.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Enalapril; Female; Humans; Hypertension; Lisinopril; Male; Radioimmunoassay; Renin

Plasma immunoreactive renin was measured by sandwich radioimmunoassay, under various physiological and pathological conditions. Enzymatic activities of active renin and trypsin-activatable inactive renin were also measured. There was a significant correlation between plasma immunoreactive renin concentration (IRRC) and total (active plus inactive) renin concentration, as estimated by enzymatic activity. In plasma from normotensive volunteers and hypertensive patients, the IRRC were 279 +/- 37 pg/ml and 268 +/- 29 pg/ml, respectively. After the intravenous injection of furosemide, the plasma IRRC in normotensive volunteers increased significantly. IRRC was significantly higher in plasma from juvenile diabetics than in plasma from age-matched disease-free children. Thus, renin secretion in children with diabetes mellitus is increased.

Topics: Adult; Angiotensinogen; Antibodies, Monoclonal; Enzyme Precursors; Humans; Hypertension; Male; Radioimmunoassay; Renin

Components of the renin-angiotensin system (plasma renin activity, total and inactive renin, angiotensinogen and angiotensin II) were examined in 90 patients with labile and stable essential hypertension before and after functional and pharmacologic tests. New data have been obtained on intrasystemic regulatory mechanisms of the pressor renin-angiotensin systems. Different patterns of plasma active and inactive renin variations in response to salt loading are demonstrated in patients with different "renin" variants of essential hypertension. Angiotensin II is shown to have a stimulating effect on angiotensinogen synthesis.

Topics: Adult; Angiotensin II; Angiotensinogen; Captopril; Female; Humans; Hypertension; Male; Middle Aged; Physical Exertion; Propranolol; Prostaglandins E; Renin; Renin-Angiotensin System; Sodium Chloride; Time Factors

Topics: Adult; Angiotensinogen; Female; Humans; Hypertension; Male; Radioimmunoassay

Topics: Angiotensin I; Angiotensinogen; Animals; Blood Pressure; Enalapril; Hypertension; Male; Rats; Rats, Inbred SHR

Topics: Adult; Aged; Angiotensinogen; Captopril; Cushing Syndrome; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Liver Cirrhosis; Male; Middle Aged; Sodium Chloride

Contraception with a vaginal ring (CVR) that delivers estradiol and levonorgestrel was used during a mean of 15.6 menstrual cycles in 12 hypertensive women. Blood pressure (BP) was measured 5 times on each visit during 2 pretreatment control cycles; during the 1st, 2nd, 4th, 6th, and from the 9th to 12th cycles of CVR use; and again after a 1-month recovery period. No significant change in BP occurred during CVR use in any of the subjects. Plasma renin substrate and antithrombin III activity did not vary significantly, which suggests the utility of administering natural estradiol via the vagina, thus avoiding the first pass effect that occurs with oral contraceptives. Significant decreases in plasma sex hormone-binding globulin, cholesterol, high density lipoprotein cholesterol, phospholipids, and triglycerides occurred, indicating an androgenic effect of levonorgestrel. We conclude that the CVR is a method of contraception that does not elevate BP in hypertensive women.. Contraception with a vaginal ring (CVR) that delivers estradiol and levonorgestrel was used during a mean of 15.6 menstrual cycles in 12 hypertensive women. Blood pressure (BP) was measured 5 times on each visit during 2 pretreatment control cycles; during the 1st, 2nd, 4th, 6th, and from cycles 9-12 of CVR use; and again after a 1-month recovery period. No significant change in BP occurred during CVR use in any of the subjects. Plasma renin substrate and antithrombin III activity did not vary significantly, which suggests the utility of administering natural estradiol via the vagina, thus avoiding the 1st pass effect that occurs with oral contraceptives. Significant decreases in plasma sex hormone-binding globulin, cholesterol, high density lipoprotein cholesterol, phospholipids, and triglycerides occurred, indicating an androgenic effect of levonorgestrel. The authors conclude that the CVR is a method of contraception which does not elevate BP in hypertensive women.

Topics: Adolescent; Adult; Angiotensinogen; Antithrombin III; Blood Pressure; Contraceptive Agents, Female; Contraceptive Devices, Female; Estradiol; Evaluation Studies as Topic; Female; Humans; Hypertension; Leukorrhea; Levonorgestrel; Lipids; Lipoproteins; Norgestrel; Prospective Studies; Sex Hormone-Binding Globulin

The mechanisms causing high blood pressure in patients with Cushing's syndrome were investigated by measurements of humoral factors and pharmacological maneuvers. Twelve patients with adrenal adenomas were studied. The mean systolic and diastolic pressures of the patients were 171 +/- 28 and 109 +/- 15 mm Hg (+/- SEM), respectively, which were significantly higher than those of normal subjects. PRA, plasma renin concentration, plasma renin substrate, plasma cortisol, plasma aldosterone, urinary kallikrein, and urinary prostaglandin E2 were measured as the humoral factors. PC values were markedly elevated in patients with Cushing's syndrome. Among the components of the renin-angiotensin system, only plasma renin substrate was increased. Urinary kallikrein and prostaglandin E2 were decreased in patients with Cushing's syndrome. Oral administration of captopril lowered blood pressure, but infusion of an angiotensin II analog did not. Furthermore, the pressor responses to infusion of both norepinephrine and angiotensin II were increased. We conclude that blood pressure is elevated in patients with Cushing's syndrome because they have enhanced pressor responses to vasoactive substances, suppression of depressor systems, and some abnormalities of the renin-angiotensin system.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Aged; Aldosterone; Angiotensin II; Angiotensinogen; Captopril; Cushing Syndrome; Dinoprostone; Female; Humans; Hydrocortisone; Hypertension; Kallikreins; Male; Middle Aged; Norepinephrine; Prostaglandins E; Renin; Renin-Angiotensin System

The 24-h pattern of plasma renin activity (PRA), inactive renin (IR), plasma aldosterone (PA) and cortisol was studied in 13 normal men and 12 male patients with essential hypertension, all of whom were older than 55 years. Following gradual habituation over 4 days to the sleep laboratory and intravenous lines, blood samples were obtained every 2 h between 0900-2100 h and every 30 min between 2100-0900 h, during which sleep was also monitored. Plasma renin activity showed a circadian rhythm in both groups, but mean levels were lower in the hypertensive subjects (0.92 +/- 0.03 versus 1.41 +/- 0.06 ng/ml per h). The circadian rhythm of PRA in older men appeared to follow the same pattern described in younger individuals. Rapid eye movement (REM) sleep was associated with a small decrease in PRA, but this link was only evident in the normotensive group. Mean 24-h IR levels were also lower in the hypertensive group (7.26 +/- 0.18 versus 15.10 +/- 0.47 ng/ml per h) but were not affected by clock-time and generally showed no association with the 24-h PRA cycle. Mean 24-h PA was closely related to cortisol but not to PRA in both groups. Mean PA levels of the two groups were similar. Thus, the PA:PRA ratio was higher in the hypertensive group. The higher basal PA:PRA ratio in older hypertensives that emerged over the 24-h study period may reflect increased sensitivity of the adrenal gland to angiotensin II (ANG II) in hypertension of the elderly.

Topics: Aging; Aldosterone; Angiotensinogen; Circadian Rhythm; Enzyme Precursors; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Potassium; Renin; Sleep, REM; Sodium

The distributions of angiotensinogen and specific renin activity were examined in the brains of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (WKY). Specific renin activity was markedly elevated in the pituitary of SHR compared to WKY. Renin levels in other regions of SHR brain were either significantly lower or similar compared to WKY. In contrast, angiotensinogen was significantly elevated in several regions of SHR compared to WKY brain. These results indicate involvement of a brain renin-angiotensin system in the development of genetic hypertension.

Topics: Angiotensinogen; Angiotensins; Animals; Brain Chemistry; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System; Species Specificity

Abnormalities of the renin-angiotensin-aldosterone system (RAAS) were observed in hypertensive patients suffering from Cushing's syndrome. In 12 patients with different etiology of Cushing's syndrome renin substrate concentration and urinary-free cortisol, as well as the circadian rhythms of plasma cortisol, aldosterone and plasma renin activity were measured. Plasma renin substrate concentrations were found elevated in all but 1 patient, while plasma renin activity was elevated, normal or lowered. Plasma aldosterone values were found in the lower normal range. A physiological rhythm of cortisol secretion was not observed in any patient with Cushing's syndrome, while plasma aldosterone was secreted episodically mostly within the normal range. We conclude that changes of the RAAS may not be predominantly responsive for hypertension in Cushing's syndrome; other factors like circulating catecholamines are probably of greater importance for the pathogenesis of blood pressure elevation in hypercortisolemic patients.

Topics: Adolescent; Adult; Aged; Aldosterone; Angiotensinogen; Blood Pressure; Child; Circadian Rhythm; Cushing Syndrome; Female; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Potassium; Renin; Renin-Angiotensin System

The effect of captopril, given in the drinking fluid, on the development of DOC-salt hypertension was analyzed. Although captopril did not prevent an increase in blood pressure (BP) elicited by DOC-salt, captopril did diminish BP in both DOC-salt and control animals. From the first week of treatment DOC-salt rats increased their fluid intake (FI). At the end of the experiment, captopril reduced this increment (655% to 357%). At the same time plasma angiotensinogen was diminished (-35%; p less than 0.001) and cerebrospinal fluid (CSF) substrate concentration increased (+33%; p less than 0.02) in DOC-salt rats, captopril did not modify these changes. In control rats captopril did not alter FI, depleted plasma angiotensinogen, (-73%; p less than 0.001), did not change the central prohormone and increased plasma renin activity (PRA) (+260%; p less than 0.001).. CSF angiotensinogen concentration changes as previously found in CNS while a clear dissociation between plasma and CSF angiotensinogen was found in DOC-salt rats. In these animals the hypertension was not clearly affected by captopril treatment. However the effect of the converting enzyme inhibitor suggests that the central renin-angiotensin system could participate in the increase in FI.

Topics: Angiotensinogen; Animals; Blood Pressure; Brain; Captopril; Desoxycorticosterone; Drinking; Hypertension; Male; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Sodium Chloride

Maternal and fetal blood samples were obtained from 10 normotensive primigravidae and 10 primigravidae with pregnancies complicated by hypertension and proteinuria. Measurements were performed of plasma renin activity (PRA), plasma renin concentration (PRC) and plasma renin substrate (PRS). PRA and PRC were significantly higher in cord artery and cord vein blood than in maternal venous blood in normotensive women, and PRS was significantly lower. PRS levels were lower in maternal plasma of hypertensive women, and, although PRC and PRA were lower in the cord blood of infants born to hypertensive women, these differences did not achieve statistical significance.

Topics: Angiotensinogen; Female; Fetal Blood; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Renin-Angiotensin System

We homogeneously purified human renin substrate from outdated bank plasma and raised antibody against it. The antibody did not cross-react with angiotensin I, angiotensin II or synthetic tetradecapeptide at concentrations of up to 160 nmol, nor did it cross-react with up to 0.2 ml of plasma from rat, rabbit or sheep. It did, however, completely cross-react with human des-angiotensin I renin substrate. A direct radioimmunoassay for human renin substrate was developed using the antibody, and the minimum detectable value of renin substrate found to be 70 pg of protein. Plasma renin substrate concentrations of normal subjects, essential hypertensive patients, diabetic patients and pregnant women were measured by direct and indirect assays. Hypertensive patients had similar concentrations of plasma renin substrate to normal subjects, whereas diabetic patients had significantly lower plasma renin substrate concentrations (p less than 0.01). The direct assay always gave a higher value than the indirect assay, and the ratios of the two assays (direct assay/indirect assay) were similar in normal subjects, hypertensive patients, diabetic patients and pregnant women.

Topics: Angiotensinogen; Angiotensins; Antibody Specificity; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Hypertension; Male; Pregnancy; Radioimmunoassay; Renin

The effects of estradiol (E2) and some other endocrine factors on rat plasma angiotensinogen (AG) have been studied. AG was determined by RIA. Both single and multiple injections of E2 to female rats were shown to cause a dose-dependent increase in AG in the blood. The effect of E2 was inhibited by cycloheximide. Multiple injections of E2 to male rats caused the same hepatic AG synthesis induction as those to female rats. Unlike E2, long-term treatment with large doses of testosterone propionate did not affect AG synthesis. AG levels in blood plasma of ovariectomized and immature female rats did not differ from those seen in mature intact rats. However, immature females were insensitive to the stimulant effect of the pharmacological doses of E2. Drastic reduction in hepatocyte sensitivity of the stimulant effect of E2 was seen in hypophysectomized female rats as well. Treatment of hypophysectomized animals with human GH, which did not affect AG levels per se, caused an almost complete recovery of hepatocyte ability to react by increasing AG synthesis in response to E2 injection. The possible role of different hormonal and genetic hepatotrophic factors in hepatocyte reactivity to the stimulant effect of E2 on AG synthesis is discussed.

Topics: Angiotensinogen; Angiotensins; Animals; Castration; Cycloheximide; Estradiol; Estrogen Antagonists; Female; Growth Hormone; Hypertension; Hypophysectomy; Liver; Male; Ovary; Pituitary Gland; Rats; Testosterone

Circulating prorenin is an enzymatically inactive form of renin, also present in kidney, which can be activated in vitro. Its biochemical properties and physiological behavior suggest that it may be a biosynthetic precursor of active renin. However, in contrast to typical prohormones, the normal plasma concentrations of prorenin are much higher than the active hormone. The purposes and functions of prorenin are unclear. It may have no further role after its secretion into the circulation. On the other hand, it may be a transport form of renin that can enter or exit cells more easily than the active form. It is also possible that the activity of the renin-angiotensin system may be regulated by the conversion of prorenin to renin in the kidney (which may be under beta-adrenergic control) or at other possible sites. Irreversible activation of prorenin appears to be a proteolytic process. In addition, acidification causes reversible activation, perhaps through a change in molecular conformation. Such reversible activation might occur in vivo by unknown mechanisms. Future studies are needed to define the biochemical processes by which increased physiological demand for renin is translated into the production of more active enzyme.

Topics: Adrenergic beta-Antagonists; Angiotensinogen; Black People; Captopril; Cold Temperature; Enzyme Precursors; Factor XII; Female; Humans; Hypertension; Kallikreins; Kidney; Kinetics; Male; Reference Values; Renin; Sex Factors; White People

Renin is a proteolytic enzyme that may be inhibited in vivo by three classes of compounds: specific antibody, general peptide inhibitors of acid proteases, and substrate analogs. With the availability of highly purified renin, specific polyclonal or monoclonal antibodies have become available. The former have already been used extensively in physiological studies with intact animals. Pepstatin is an inhibitor of many acid proteases. Its in vivo application has been retarded by relative insolubility, but recent chemical modifications, particularly the addition of charged amino acids at the carboxy terminus, have rendered it more useful. The minimal substrate for renin is an octapeptide segment of the protein substrate: His-Pro-Phe-His-Leu-Leu-Val-Tyr. Variants of this sequence have resulted in competitive inhibitors that are useful in vivo. Effectiveness of a given peptide varies among different species of animals, possibly because of different substrate specificity. To support this hypothesis, it has been reported that the amino acid sequences of angiotensinogens around the site where renin cleaves may vary among species. Effectiveness of inhibitors is also dependent on the hydrophobicity of amino acids near the cleavage site. Recently, remarkably active inhibitors have been synthesized by reducing the peptide bond that is cleaved by renin. Studies with monkeys show that a peptide renin inhibitors may cause hypotension after sodium depletion and normalize blood pressure in Goldblatt hypertension to the same degree as a converting-enzyme inhibitor.

Topics: Amino Acid Sequence; Angiotensin I; Angiotensinogen; Animals; Blood Pressure; Enzyme Inhibitors; Heart Rate; Humans; Hypertension; Kinetics; Macaca fascicularis; Oligopeptides; Rats; Renin; Substrate Specificity; Swine; Teprotide

Evidence has accumulated that systemic administration of converting enzyme inhibitors (CEI) such as captopril, MK 421 or SA 446 not only produces an inhibition of the plasma renin angiotensin system (RAS), but also of the RAS in various target organs which are relevant for blood pressure (BP) regulation. A potential target organ is the brain, where a local CE inhibition could contribute to the BP lowering action of CEI. CE in the brain can be inhibited by intracerebroventricular (i.c.v.) injection of CEI as evidenced by an inhibition of the pressor and drinking responses to i.c.v. angiotensin I (ANG I) or renin and by potentiation of the pressor responses to i.c.v. bradykinin. Site of the inhibition is not only the cerebrospinal fluid but also periventricular brain tissue such as the hypothalamus. I.c.v. injection of captopril at doses which inhibit brain CE but do not leak into the peripheral blood were shown to lower BP in conscious stroke-prone spontaneously hypertensive rats (SHRSP), but not in normotensive Wistar Kyoto (WKY) controls. Acute peripheral administration of CEI can produce an inhibition of brain CE. This was shown by an attenuation of the drinking responses to i.c.v. ANG I and renin and by direct measurements of CE activity in brain tissue. Chronic oral treatment with CEI produces changes of brain RAS parameters which suggest an inhibition of ANG II formation in the brain.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Brain; Humans; Hypertension; Injections, Intraventricular; Rats; Receptors, Angiotensin; Renin; Renin-Angiotensin System

The hypertensinogenic effects of 6 beta-hydroxyandrostenedione (6 beta-OH-A-dione), which we reported as an amplifier of the kaliuretic action of aldosterone on the basis of the results obtained in bioassays using adrenalectomized rats, were evaluated in rats with the adrenals and compared with those of 19-hydroxyandrostenedione (19-OH-A-dione), an amplifier of the sodium-retaining action of aldosterone. The administration of 6 beta-OH-A-dione to rats with the adrenals caused sodium-retention as the administration of 19-OH-A-dione did and the 6 beta-OH-A-dione treated rats developed high blood pressure, suppressed plasma renin activity and low plasma aldosterone, corticosterone and 11-deoxycorticosterone concentrations as the 19-OH-A-dione treated rats did. The results demonstrate that 6 beta-OH-A-dione works as a hypertensinogenic agent in the presence of the adrenal cortex and causes the hypertensive state simulating mineralocorticoid excess. The present paper adds further evidence for the hypertensinogenic effects of amplifiers of the action of aldosterone and suggests the importance of amplifiers of the action of aldosterone in the etiology of human hypertension.

Topics: Aldosterone; Androstenedione; Angiotensinogen; Angiotensins; Animals; Corticosterone; Hypertension; Male; Potassium; Rats; Rats, Inbred Strains; Renin; Sodium

Angiotensinogen was measured in the brain and cerebrospinal fluid (CSF) of spontaneously hypertensive rat (SHR) and the normotensive Wistar-Kyoto strain at 4, 7 and 16 weeks of age. Levels of angiotensinogen were elevated in a number of areas of SHR, primarily in the 4 and 7 week old animals. CSF levels did not correlate with the brain levels. These results suggest that the regulation of the brain angiotensin system maybe altered during the development of hypertension.

Topics: Angiotensinogen; Angiotensins; Animals; Blood Pressure; Brain; Histocytochemistry; Hypertension; Immunochemistry; Immunoenzyme Techniques; Male; Rats; Rats, Inbred Strains

Several interventions known to alter plasma renin substrate in rats such as nephrectomy (NX), adrenalectomy (ADX) and glucocorticoid treatment changed the angiotensinogen content in the cerebrospinal fluid (CSF) in the same direction. However, peripheral and central angiotensinogen could be dissociated from each other by ADX and NX in combination, as well as by chronic converting enzyme blockade. The regulation of brain angiotensinogen was further investigated in stroke-prone spontaneously hypertensive rats (SHR-sp) in comparison with normotensive Wistar Kyoto (WKY) rats. The angiotensinogen levels of the anterior hypothalamus and of the septal area showed strain and age-related differences. Chronic converting enzyme blockade, which kept SHR-sp normotensive, stimulated angiotensinogen in the anterior hypothalamus of both SHR-sp and WKY rats, but suppressed plasma renin substrate. A specific radioimmunoassay (RIA) for renin substrate of rat plasma also recognized the CSF angiotensinogen, and a linear correlation existed between direct and indirect measurements. In conclusion, angiotensinogen in the central nervous system appears to be immunologically similar to plasma angiotensinogen. Its regulation is not directly related, however, to circulating renin substrate, although adrenal steroids stimulate both central and peripheral angiotensinogen. A differential regulation of angiotensinogen in the brain of SHR-sp as compared to WKY is evident and could be linked to blood pressure control.

Topics: Aging; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Brain; Captopril; Cerebrovascular Disorders; Hypertension; Male; Rats; Rats, Inbred Strains

Topics: Adult; Aged; Angiotensin II; Angiotensinogen; Angiotensins; Blood Pressure; Captopril; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Proline; Renin; Time Factors; Vasopressins

Topics: Adult; Aldosterone; Angiotensinogen; Blood Pressure; Captopril; Drug Interactions; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Oligopeptides; Posture; Renin; Sodium

The blood pressure level and the renin-angiotensin system were investigated in 24 menopausal women (12 normotensive and 12 hypertensive) before, during and after six months of treatment with either oestradiol or trisekvens (sequential preparation containing oestradiol, oestriol and norethisterone acetate). In the normotensive women no significant alterations in systolic or diastolic blood pressure were found during treatment for six months. In the hypertensive women systolic blood pressure fell significantly during treatment with oestradiol as well as with trisekvens, while diastolic pressure did not change. All individual variations of blood pressure were small. The plasma concentrations of renin, angiotensin II and aldosterone remained unchanged during the treatments. A statistically significant increase in plasma renin substrate concentration was observed in all groups with the exception of the normotensive women treated with oestradiol. Menopausal symptoms in hypertensive women may safely be treated with natural oestrogens on the same indications as used for normotensive women.

Topics: Adult; Angiotensinogen; Blood Pressure; Climacteric; Drug Combinations; Estradiol; Estriol; Estrogens; Follicle Stimulating Hormone; Humans; Hypertension; Male; Middle Aged; Norethindrone; Renin-Angiotensin System

This study examines the role of gluco- and mineralcorticoids in the regulation of the renin-angiotensin system and blood pressure in the spontaneously hypertensive rat (SHR). Effects of adrenalectomy and selective treatment with either aldosterone (30 micrograms/kg/day) or dexamethasone (60 micrograms/kg/day) on plasma renin substrate, active renin (PRA), total renin and blood pressure were studied in 10 week old SHR and control WKY rats. Systolic blood pressure was moderately lower in adrenalectomized rats (129 +/- 2 mm Hg vs 137 +/- 4 mm Hg in control WKY and 145 +/- 4 mm Hg vs 160 +/- 3 mm Hg in control SHR) but could be restored to the control range by aldosterone. Dexamethasone repletion induced substantial increments of systolic blood pressure to comparable levels in both species (202 +/- 8 mm Hg in WKY and 192 +/- 6 mm Hg in SHR). Renin substrate was markedly lower in adrenalectomized, saline repleted rats. This could be reversed by dexamethasone in both species and by aldosterone in WKY rats only. Both PRA and total renin were higher (p less than 0.01) in the adrenalectomized, saline repleted state. This increase was not observed in aldosterone repleted rats. However, dexamethasone inhibited the adrenalectomy associated increase of PRA and total renin in SHR but not in WKY rats. Differences in blood pressure between SHR and WKY persist even in adrenalectomized state despite comparable stimulation of the renin system. Conversely, while blood pressure of both species responds similarly to selective corticosteroids therapy, the response of the renin-angiotensin system in SHR and WKY rats is distinct. Therefore factors other than the adrenal gland and the renin system must be involved in the determination of the high blood pressure in SHR.

Topics: Adrenal Cortex Hormones; Adrenal Glands; Adrenalectomy; Aldosterone; Angiotensinogen; Animals; Blood Pressure; Body Weight; Dexamethasone; Hypertension; Male; Rats; Rats, Inbred Strains; Renin-Angiotensin System

We have previously reported that estrogens have the potential to induce new forms of renin substrate in addition to elevating the major circulating form of this protein. One of these estrogen-induced forms had a molecular weight in excess of 150,000. In this study we have compared the plasma concentration of the high-molecular-weight renin substrate in normotensive women receiving estrogen therapy and women with estrogenic hypertension. A statistically significant elevation of this protein was associated with estrogenic hypertension and normotensive pregnant women at term. This form of renin substrate differed from the major form with respect to electrophoretic mobility, isoelectric point, and immunologic cross-reactivity. In addition, kinetic analysis indicated that this high-molecular-weight substrate has a significantly higher affinity for the enzyme renin than the major circulating form (Km = 1800 +/- 290 versus 3520 +/- 260 ng angiotensin I equivalents/ml). These results suggest that in addition to renin substrate concentration, substrate composition may play an important role in blood pressure regulation.. This study investigates whether qualitative rather than quantitative differences in renin substrate were associated with estrogen induction of hypertension by comparing the plasma concentration of high molecular weight renin substrate (HMS) in 18 healthy normotensive, nonpregnant women aged 35-50 taking no medication; 20 normotensive subjects receiving estrogens as oral contraceptives (OCs) or ethinyl estradiol (EE) 50 mcg; and 5 women on OCs or EE 50 mcg who became hypertensive on estrogen therapy. A significant increase in renin substrate was evident in all women with elevated plasma estrogen levels. The difference in total renin substrate levels of normotensive and hypertensive subjects was not statistically significant. HMS differed from the normal molecular weight substrate (NMS) in electrophoretic mobility, isoelectric point, and immunologic cross-reactivity. Kinetic analysis indicated that it also had a significantly higher affinity for the enzyme renin than the major circulating form (Km=1800 +or- 290 versus 3520 +or- 260 ng angiotensin I equivalents/ml). The results suggest that substrate composition may play an important role in blood pressure regulation.

Topics: Adult; Angiotensinogen; Angiotensins; Contraceptives, Oral; Estrogens; Female; Humans; Hypertension; Middle Aged; Molecular Weight; Pregnancy; Stimulation, Chemical

Human angiotensinogen has been purified from outdated blood bank plasma. The purified angiotensinogen has a specific angiotensin I (Ang I) content of 20.7 micrograms Ang I/mg protein and contains only one amino-terminal amino acid, aspartic acid. However, it exhibits two bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with apparent molecular weights of 61,400 and 65,400. It is concluded that these bands represent different forms of angiotensinogen because the specific Ang I content is equivalent to the theoretical Ang I content. Analysis of the purified angiotensinogen showed it to contain 14% carbohydrate.

Topics: Amino Acid Sequence; Amino Acids; Angiotensinogen; Angiotensins; Animals; Electrophoresis, Polyacrylamide Gel; Female; Humans; Hypertension; Molecular Weight; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Species Specificity; Swine

The missing link in the evidence for an active endogenous renin angiotensin system in the brain has been the demonstration of local angiotensin synthesis in the central nervous system in vivo. In this report the extraction and characterization of angiotensin I and angiotensin II from the brain of rats is described. The accumulation of angiotensin I was enhanced in hypertensive rats when the conversion to angiotensin II was blocked in vivo by the converting enzyme inhibitor captopril.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Angiotensins; Animals; Brain; Hypertension; Nephrectomy; Radioimmunoassay; Rats

The effects of converting enzyme inhibition on plasma renin substrate concentration were studied in man and rat. This study use new direct radioimmunoassays of angiotensinogen completing the classical enzymatic methods. In human investigation converting enzyme is inhibited after Captopril treatment. Our results demonstrated that resulting increase of plasma renin concentration enhanced the consumption of renin substrate as shown by the fall of angiotensinogen levels measured by indirect method. In the rat, we observed the same drop of renin substrate during MK421 administration. The fall of angiotensinogen levels, measured by indirect method, was not in agreement with results of direct radioimmunoassay. This discrepancy can be explained by the accumulation of des-angiotensin I-angiotensinogen in plasma. These modifications are potentiated by sodium depletion.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Captopril; Humans; Hypertension; Male; Methods; Peptide Fragments; Proline; Radioimmunoassay; Rats; Rats, Inbred Strains; Renin

In 10 severely hypertensive patients, on a low sodium diet, converting enzyme inhibition increased plasma renin activity and decreased plasma renin substrate. The use of direct radioimmunoassays for both the enzyme and its substrate showed that the number of immunoreactive renin molecules increased from 11.3 +/- 4.9 to 31.7 +/- 25.3 pmol 1(-1) whereas the number of immunoreactive renin substrate molecules decreased from 1.04 +/- 0.35 to 0.74 +/- 0.16 mumol 1(-1). The direct radioimmunoassay for angiotensinogen gave higher values than the direct enzymatic assay, and during converting enzyme inhibition, the difference between both methods increased in proportion to the rise in circulating renin. It is concluded that the difference between the renin substrate radioimmunoassay, which measures angiotensinogen and des-angio I-angiotensinogen, and the renin substrate enzymatic assay which only measures "active" substrate, is an index of the increased consumption of renin substrate, in a situation where the fall in angiotensin II enhances renin release and decreases renin substrate release.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Enzyme Activation; Enzyme Precursors; Humans; Hypertension; Radioimmunoassay; Renin

As a discrepancy exists between two reports from our laboratory on plasma renin activity (PRA) in spontaneously hypertensive rats (SHR), we undertook to examine the reasons for this discrepancy. PRA in SHR at 15 weeks of age was determined by two different methods, utilizing the procedures of Boucher et al or of Haber et al. For normotensive controls, Donryu (DON) and Wistar-Kyoto (WKY) rats were used. By Boucher's method, PRA in SHR was significantly lower than in DON, but did not differ from WKY. By Haber's method, PRA in SHR did not significantly differ from DON or WKY. However, the value in DON was significantly higher than in WKY. The present study basically confirmed our previous results, concluding that PRA in SHR at 15 weeks of age is within the normal range. A previous suggestion that PRA in SHR is suppressed as a result of blood pressure elevation must be revised, because it was derived from results considering only the DON strain as the control.

Topics: Angiotensinogen; Animals; Hypertension; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Renin

It can be estimated that women using hormonal contraceptives develop hypertension at a rate of 1% to 2%. This occurs within 6 to 12 weeks after beginning the contraceptive. As for the extent of the elevation, it varies from slight elevations of systolic and/or diastolic pressure up to serious, even malignant hypertension including nephrosclerosis. Although the latter is rare, it underlines the importance of keeping careful check on women taking these pills. After cessation of the pill the blood pressure drops in a greater or lesser proportion of the women within 3 to 6 months. Some authors say 8-12 months. No antihypertensive therapy is required for this. The blood pressure elevation correlates regularly with parallel changes in the renin-angiotensin-aldosterone-system. This is caused mainly by the estrogen component of the hormonal contraceptive. It is manifested by overproduction of angiotensinogen in the liver with subsequent elevation of angiotensin II. Finally there is a sharp vasoconstriction and increase in aldosterone production which cause systemic blood pressure elevation. It can be postulated that sodium retention, and genetic predisposition to react to elevation of the whole-body sodium content by an increase in blood pressure, are determining for the pathogenesis of this condition. The appropriate conclusions should be drawn as concerns the prescription of hormonal ocntraceptives in medical practice.

Topics: Angiotensin II; Angiotensinogen; Contraceptives, Oral; Contraceptives, Oral, Hormonal; Estrogens; Female; Humans; Hypertension; Liver; Renin-Angiotensin System; Sodium; Vasoconstriction

The recent development of several inhibitors of the renin-angiotensin system has perfected our knowledge of the part played by this system in the control of physiological and pathological arterial pressure. Peptides inhibiting angiotensin II, such as Sar1, Ala8 angiotensin II, block the peripheral effects of angiotensin on vascular renal and adrenal receptors. Inhibition of the conversion enzyme, notably with captopril, prevents the formation of angiotensin II from angiotensin I and also results in accumulation of a vasodilator and natriuretic peptide: bradykinin. Finally, it is now possible to inhibit more specifically the reaction of renin with its substrate, angiotensinogen, by using pepstatin or its derivatives, or peptide analogues of the substrate. The use of these inhibitors, especially captopril (so far the most studied), has made it clear that renin plays a part in experimental and human essential hypertension and participates in the control of arterial blood pressure in subjects with normal sodium intake.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Captopril; Humans; Hypertension; Rats; Renin

1. We have measured plasma concentrations of renin, renin substrate and angiotensins I and II as well as plasma renin activity in nine patients with severe or malignant hypertension during treatment with captopril, hydrochlorothiazide and propranolol. 2. On captopril and hydrochlorothiazide the plasma concentrations of renin substrate and angiotensin II decreased markedly, while renin and angiotensin I levels were increased. 3. The changes in renin substrate concentration suggest a consumption of substrate induced by an increased renin release. Further, the positive feedback of angiotensin II on hepatic renin substrate synthesis may be inhibited. 4. The sequential changes in renin release during captopril treatment should be monitored by measuring plasma renin concentration since plasma renin activity measurements will be profoundly influenced by the marked changes in plasma renin substrate concentration.

Topics: Angiotensinogen; Angiotensins; Captopril; Drug Therapy, Combination; Humans; Hydrochlorothiazide; Hypertension; Methods; Proline; Propranolol; Renin

The effects of dexamethasone (DEX) on systolic blood pressure, sodium balance and the renin-angiotensin system were studied in rats. DEX significantly increased systolic blood pressure within three days of its administration, but this effect of DEX on blood pressure was not enhanced by concurrent use of saline solution. In DEX-treated rats, urine volume was significantly increased and urinary sodium excretion showed a tendency toward a slight increase compared to control rats. On the 8th day of DEX administration, plasma renin substrate (PRS) was significantly elevated compared to control rats, whereas plasma aldosterone concentration (PAC) was not significantly different from that of control rats. These results suggest that hypertension induced by DEX may not be dependent on sodium retention or activation of the renin-angiotensin system.

Topics: Angiotensinogen; Angiotensins; Animals; Blood Pressure; Dexamethasone; Hypertension; Kinetics; Male; Rats; Rats, Inbred Strains; Renin; Sodium

The angiotensin substrate analog Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys has no significant effect on blood pressure in sodium-replete monkeys (Macaca fascicularis) but blocks the pressor response to infused human renin. Pressor responses to angiotensin I and angiotensin II are not attenuated. In five studies in sodium-depleted monkeys, an infusion of 2 mg of the peptide per kg of body weight resulted in a reduction of mean arterial pressure (MAP) from 105 +/- 4 to 79 +/- 3 mm Hg, which is not significantly different from the response to 1 mg of the angiotensin I-converting enzyme inhibitor teprotide per kg. In uninephrectomized monkeys, inflation of a suprarenal aortic cuff caused an increase in MAP from 107 +/- 3 to 131 +/- 3 mm Hg. Infusion of 0.6 mg of the renin-inhibitory peptide per kg was followed by a return of blood pressure to 107 +/- 4 mm Hg--a depressor response similar to that observed with teprotide. This specific in vivo inhibitor of renin can now be applied to a wide variety of physiologic studies.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Macaca fascicularis; Male; Oligopeptides; Peptidyl-Dipeptidase A; Renin; Sodium; Teprotide

Pre-eclampsia and 'essential' hypertension in pregnancy require to be studied separately. Their haemodynamic characteristics need to be determined and the effects of antihypertensive therapy and blood volume expansion explored. Diuretics should be used in pre-eclampsia only to treat cardiac failure. Hydrallazine may be contraindicated if cardiac failure is imminent. The role of propranolol remains undecided and a controlled trial is required. Studies of the renin-angiotensin system which take into account the various factors that alter renin secretion may prove useful.

Topics: Angiotensinogen; Blood Pressure; Female; Hemodynamics; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Cushing Syndrome; Diuretics; Electrophoresis, Polyacrylamide Gel; Female; Humans; Hypertension; Isoelectric Focusing; Kinetics; Liver Cirrhosis; Molecular Weight; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Regression Analysis; Uremia

Topics: Adult; Aldosterone; Angiotensin II; Angiotensinogen; Blood Pressure; Humans; Hypertension; Potassium; Renin

Topics: Adult; Aged; Angiotensin II; Angiotensinogen; Endopeptidases; Enzyme Activation; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Renin; Shock, Cardiogenic

Topics: 18-Hydroxydesoxycorticosterone; Adenoma; Adolescent; Adrenal Cortex Neoplasms; Adrenal Glands; Adult; Aged; Aging; Angiotensin II; Angiotensinogen; Carbon Dioxide; Corticosterone; Desoxycorticosterone; Female; Humans; Hyperaldosteronism; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Potassium; Renin; Sodium; Urea; Vascular Diseases

The objective of this investigation was to determine whether heterogeneity of plasma renin substrate could be observed in states of steroid excess and various forms of hypertensive disease. In states of stimulated renin substrate production by estrogens or glucocorticoids, multiple forms of renin substrate were apparent when stimulation was excessive. Stimulation of substrate production caused by uremia associated with hypertension showed similar results. None, or only trace quantities of the additional forms of renin substrate were evident in subjects with normal or suppressed levels of plasma renin substrate. The additional forms of renin substrate could be distinguished from the normal form on the basis of cross-reactivity with a specific antiserum to the normal form, electrophoretic mobility, and kinetic rate constants. Differences in rate constants of the various forms of plasma renin substrate may account for the altered rate of the renin reaction associated with several states of hypertension. In plasma of patients with renovascular hypertension, significant quantities of a protein which cross-reacted with the antiserum but could not generate angiotensin I were observed.

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Cushing Syndrome; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Pregnancy; Uremia

The blood pressure response to the angiotensin II analog 1-sar-8-ala-angiotensin II, or saralasin, was studied in five patients with clinical and laboratory evidence of Cushing's syndrome. Plasma renin activity, plasma renin substrate, and plasma renin concentration were measured in all five patients. The renin system and the response to saralasin were measured after furosemide administration. Plasma aldosterone was measured after infusion of 2 liters normal saline. All patients studied showed a hypotensive response to saralasin, the mean BP changing from 163/108 mm Hg to 130/85 mm Hg (P less than 0.02). There was a significant elevation of the plasma renin activity and plasma renin concentration in the patients compared to normal subjects, although plasma renin substrate was not significantly different from normal values. There was normal suppression of plasma aldosterone after the infusion of 0.9% saline. The findings indicate that the hypertension of these patients with Cushing's syndrome was mediated in large part by angiotensin II.

Topics: Adrenal Glands; Adrenalectomy; Adult; Aldosterone; Angiotensin II; Angiotensinogen; Blood Pressure; Cushing Syndrome; Female; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Renin; Saralasin

Topics: Angiotensinogen; Animals; Chromatography, Affinity; Enzyme Precursors; Humans; Hydrogen-Ion Concentration; Hypertension; Immune Sera; Molecular Weight; Pepstatins; Renin

Plasma renin substrate, a widely measured parameter of the renin reaction, is quantitated indirectly by the measurement of liberated angiotensin I upon exhaustive incubation of plasma with added renin. To overcome methodological problems of this assay system, we have developed a direct radioimmunoassay for this plasma protein using renin substrate purified from pooled plasma of normotensive subjects as the antigen. Comparison of substrate quantitated by the two assay systems (direct and indirect) indicates a 1:1 correlation with the exception of certain subjects with elevated substrate levels induced by estrogen therapy. To study the possibility of multiple substrate forms, we have made a comparison of substrate quantitated by both radioimmunoassays in conjunction with electrophoresis of plasma on polyacrylamide gel. One major form of substrate with a retardation factor (Rf) = 0.60 was found in normotensive and essential hypertensive subjects which gave a 1:1 correspondence on quantitation by the two methods. In contrast, six of 16 women on oral contraceptives demonstrated three forms of substrate (Rf = 0.16, 0.35, and 0.60) on electrophoresis. Substrate with Rf = 0.16 and 0.35 did not cross-react with the antiserum prepared against substrate from normotensive subjects, implying structural differences in these proteins.

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Humans; Hypertension; Methods; Radioimmunoassay

Renin activity, concentration, substrate and reactivity were determined in normal subjects as well as in hypertensive subjects with suppressed and normal plasma renin activity. Renin substrate measurements were similar in all groups. Renin reactivity, a measure of circulating modifiers of the renin reaction, was significantly increased in both hypertensive groups. Reactivity was significantly greater in the normal renin hypertensive group than the low renin hypertensive group. Renin concentration was significantly suppressed in both hypertensive groups, but to a greater degree in the low renin hypertensives. These findings suggest that plasma renin concentration may be suppressed in most hypertensive subjects. Furthermore, plasma renin activity may be "normalized" in most hypertensive subjects by the effect of circulating modifiers of the renin reaction. While renin reactivity in the plasma of low-renin hypertensive subjects is accelerated to a lesser degree than that of the normal-renin hypertensives, this finding alone does not explain the low plasma renin activity.

Topics: Angiotensinogen; Humans; Hypertension; Renin; Sodium

The influence of pH and angiotensinase inhibitors on the in vitro generation of angiotensin I during PRA measurements has been investigated. PRA values obtained at pH 5.7 are higher than those obtained at pH 7.4. At pH 5.7, values obtained using diisopropylfluorophosphate (DRP 9 mM) as an angiotensinase inhibitor are higher than values obtained with a mixture of dimercaprol (BAL, 1.6 mM) and hydroxyquinoline (8-OHQ, 3 to 4 mM). Since the two methods for inhibiting angiotensinase are completely and equally efficient, it is suggested that these inhibitors might interfere with the renin angiotensinogen reaction. Significant correlations are observed between the PRA values obtained by the different methods which have been studied. Using an incubation pH of 5.7, and BAL and 8-OH quinoline as angiotensinase inhibitors, the distribution of PRA values in a population of 124 hospitalized hypertensive patients ingesting a normal sodium diet had been studied, and it has been demonstrated that the sensitivity of this method of measurement can detect small changes in PRA in patients with low renin activity.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Angiotensin II; Angiotensinogen; Dimercaprol; Humans; Hydrogen-Ion Concentration; Hypertension; Isoflurophate; Methods; Middle Aged; Oxyquinoline; Posture; Protease Inhibitors; Radioimmunoassay; Renin; Time Factors

We previously demonstrated an inactive form of renin, termed prorenin, in the plasma of normal, hypertensive and anephric patients. Prorenin activity can be determined in plasma from the total renin activity after activation, minus the prior endogenous plasma renin activity. In the present study, conditions for cryoactivation of prorenin have been defined. Plasma prorenin is slowly converted to active renin-like material at -5 degrees C at pH 7.4. Activation takes four days and does not occur at pH 5.0. The degree of activation increases above pH 5 and is greatest between pH 7 and pH 9. Thus, almost no cryoactivation of prorenin occurs at the pH optimum for renin (5.7) in contrast to maximum activation at pH 7.4. No activation has been observed in the frozen state, but it does occur with decreasing rapidity at temperatures from -5 degress to +4 degress C. Since blood samples obtained for the determination of plasma renin activity are routinely chilled upon collection by most laboratories, some activatin of prorenin most likely occurs in all routine renin assays. The pH optimum of the enzymatic reaction of the activated prorenin in plasma is 5.8, the same as for renal renin, and the shape of the pH optimum curve is similar to that of renal renin added to human plasma. In a group of 23 normal subjects with plasma renin activity of 3.5 +/- 2.9 (SD), the activated prorenin increment was found to be significantly higher, 6.3 +/- 5.0 (SD) ng/ml/hour. Unlike plasma renin activity, prorenin activity in these normal subjects was directly related to the concentration of renin substrate (p less than 0.001). When the actual "concentration" of prorenin was calculated using renal renin as the reference standard, a direct relationship was also found between the concentration of prorenin and renin substrate (p less than 0.01). The observed relationship between prorenin and renin substrate concentrations might be a consequence of their regulation by common factors.

Topics: Angiotensin II; Angiotensinogen; Cold Temperature; Female; Freezing; Humans; Hydrogen-Ion Concentration; Hypertension; In Vitro Techniques; Kidney; Male; Renin; Time Factors

The renin-angiotensin system shows a marked increase in activity in normal pregnancy, with the major changes occurring in the first trimester. Evidence is presented to show that there is a physiologically inactive prorenin present in the plasma during pregnancy that achieves highest levels in the first half of pregnancy. The significance of this "acid-activated" renin has yet to be determined. Plasma angiotensin II levels are elevated throughout normal pregnancy, and a significant positive relationship has been established between maternal venous and cord venous levels at delivery. Recent studies on plasma AII levels in pregnancy hypertension have shown a positive correlation between diastolic blood pressure and plasma AII, and there is evidence that the high circulating levels of angiotensin may result in a feed-back suppression of renal renin release. Studies on the fetal circulation at delivery have also shown high levels of AII in the cord venous blood of infants born to mothers with pregnancy hypertension. Despite the increased level of activity of the renin-angiotensin system in normal pregnancy, sodium homeostasis is maintained. The possible reasons for the increased activity are discussed briefly.

Topics: Angiotensin II; Angiotensinogen; Endopeptidases; Female; Fetal Blood; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Sodium

A moderate elevation of the daily excretion of free noradrenaline and adrenalin is observed in chronic circulatory insufficiency, beginning with Stage IIA. The catecholamines metabolism is elevated, as shown by the daily excretion of normethanpherine and methanpherine and of vanillyl-mandelic acid. The activity of renin and angiotensinases was growing along with the progressing cardiac insufficiency. The blood level of angiotensinogen was decreasing, especially in patients with Stage IIB and III of decompensation. The daily excretion of aldosterone was growing along with the development of cardiac insufficiency. The functional state of the glucocorticoid function of the adrenal cortex was of a phased nature in cases of circulatory insufficiency. The study of the functional state of the epiphysis was conducted by way of determining the blood level of melatonine and of its daily excretion. In Stages I and IIA the level of this hormone was clearly elevated, in Stages IIB and III -- decreased as compared with the initial and normal levels. The plasma level of the antidiuretic hormone was distinctly growing, beginning with Stage IIB, reaching its maximal values in Stage III.

Topics: 17-Ketosteroids; Adult; Aged; Aldosterone; Angiotensinogen; Coronary Disease; Cortisone; Endopeptidases; Epinephrine; Female; Heart Failure; Humans; Hydrocortisone; Hypertension; Male; Melatonin; Metanephrine; Middle Aged; Norepinephrine; Normetanephrine; Renin; Tetrahydrocortisol; Tetrahydrocortisone; Vanilmandelic Acid

Compared with a group of normal pregnant women, matched for age, parity, posture, and length of gestation, women with hypertension and proteinuria in the last trimester had significantly lower plasma concentrations of renin, renin substrate and angiotensin II. Plasma aldosterone and DOC concentrations were also lower in the hypertensive group. The plasma levels of cortisol, corticosterone, and ADH showed no significant difference. Plasma renin concentration was raised throughout normal pregnancy, and part of this increase appeared to be due to the presence of an inactive form of renin. Plasma concentrations of renin substrate, angiotensin II, and aldosterone were also raised in normal pregnant women, but concurrent measurement of these substances showed no significant relationship between them, renin, and plasma electrolytes in mid- or late gestation. A study of five women in the weeks immediately after conception showed increases in plasma angiotensin II and aldosterone concentrations, which were significantly related at this very early stage of pregnancy. Total 24-hour urinary sodium increased gradually from about two weeks after gestation to the end of the study five weeks later. This increase was due mainly to a rise in overnight sodium excretion, with a fall in the day/night ratio. No relationship was found between plasma angiotension II or aldosterone concentrations and day, night, or total 24 hour sodium excretion.

Topics: Adrenal Cortex Hormones; Aldosterone; Angiotensin II; Angiotensinogen; Arginine Vasopressin; Corticosterone; Desoxycorticosterone; Female; Humans; Hydrocortisone; Hypertension; Ovulation; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, First; Renin; Sodium; Vasopressins

To investigate the role of components of the renin-angiotensin-aldosterone system and plasma progesterone concentrations in the pathophysiology of hypertension in pregnancy, sequential measurements were made throughout pregnancy in 45 normotensive subjects, 41 other pregnant patients in whom hypertension became manifest only during pregnancy and 26 patients with chronic hypertension antedating pregnancy. Among the normotensive subjects plasma renin activity and substrate, plasma aldosterone and progesterone concentrations were elevated as early as the sixth week of gestation. While consistent, progressive, further increases were noted in renin substrate, aldosterone and pregesterone concentrations during pregnancy, plasma renin activity did not continue to rise. In both hypertensive groups, plasma renin activity and aldosterone concentration were significantly suppressed during the last trimester despite levels of renin substrate and progesterone that were not significantly different than those observed in normotensive pregnancy. These observations confirm earlier studies reporting suppression near term of plasma renin activity in toxemia and indicate from these prospective observations that they are secondary effects. These studies, in addition, demonstrate parallel suppression of plasma aldosterone concentration in toxemia. The current report also indicates that this suppression is not due to a decrease in renin substrate concentration and that a hypothesized deficiency of plasma progesterone, which was not observed in the hypertensive subjects, does not play a permissive role in the development of hypertension.

Topics: Aldosterone; Angiotensin II; Angiotensinogen; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Progesterone; Renin

The demonstration that the components required for the generation of angiotensin II are present in the brain has led to the proposal that there is a brain renin-angiotensin system. To test this hypothesis, experiments were performed to determine if biologically active amounts of angiotensin II are formed when renin is injected into the cerebral ventricles. The effects of central administration of agents known to block the peripheral renin-angiotensin system were also investigated. It was shown that intraventricular renin increased water intake, blood pressure and ADH secretion and that these effects were blocked by saralasin. These findings indicated an interaction between injected renin, brain angiotensinogen and converting enzyme, resulting in the formation of angiotensin II in physiologically active concentrations. However, these experiments did not demonstrate a role for endogenous brain renin activity. Central administration of saralasin in normal animals did not decrease water intake, blood pressure or ADH secretion. These studies thus failed to demonstrate a physiological role for the proposed brain renin-angiotensin system in controlling water balance and blood pressure.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Brain; Dogs; Drinking; Hypertension; Rats; Renin; Saralasin; Swine; Vasopressins

An increase in plasma renin activity was demonstrated in plasma from normal subjects and most patients with essential hypertension after prolonged storage of the plasma at -20 degrees C. No change in renin substrate concentration was observed after storage for 12 months, and the rate of angiotensin generation during incubation with a fixed amount of added human renin was not increased. It therefore seems unlikely that the observed increase in renin activity was due to changes in plasma activators or inhibitors. The data are consistent with the activation of an inactive form of renin, tentatively called "prorenin" in normal subjects averaged from 1 to 2 ng/ml/hr, and did not change during sodium deprivation. However, three of four patients studied who had low-renin essential hypertension secreted abnormally large amounts of "prorenin" in response to sodium depletion. In these patients, subsequent sodium administration was associated with a return of "prorenin" to baseline levels.

Topics: Angiotensin II; Angiotensinogen; Drug Storage; Enzyme Activation; Enzyme Precursors; Female; Freezing; Humans; Hydrogen-Ion Concentration; Hypertension; In Vitro Techniques; Male; Renin; Sodium; Time Factors

The rate of angiotensin generation with added renin in plasma from patients with benign essential hypertension has been shown to be higher than in plasma from norm ensive controls. An index of the angiotensin generation rate in relation to to al plasma renin substrate (PRS-r index) has been defined which allows for screening for "activated" plasma. In hypertensive subjects, this index was shown to be higher than that of the normotensive subjects (61 plus or minus 2.4 SE, and 45 plus or minus 5 SE). The index did not correlate with the absolute levels of blood pressure, 24-hour sodium excretion, or plasma renin activity in hypertensive subjects either during the control period or during acute alterations of blood pressure, but was shown to respond in a parallel fashion with chronically induced changes in blood pressure and circulating levels of angiotensin I. By the use of an isolated system of human renin and homologous renin substrate, we have demonstrated that plasma from hypertensive subjects contains a modifier of the renin reaction which increases both V-max and Km of the system, behaving as an uncompetitive activator. No significant change was noted with the addition of normal plasma to the same isolated system.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Contraceptives, Oral; Diuretics; Enzyme Activation; Functional Laterality; Haplorhini; Humans; Hydrochlorothiazide; Hypertension; In Vitro Techniques; Kinetics; Renal Artery Obstruction; Renin; Sodium; Spironolactone

After addition of exogenous human renin, the in vitro rate of angiotensin I generation is faster in plasma of patients with chronic renal insufficiency and, to a lesser extent, in plasma of patients with essential hypertension than in plasma from normotensive control subjects. The increased reactivity of renin in hypertensive and uremic plasma is not related to differences of endogenous renin activity, angiotensinase activity, renin substrate concentration, or substrate reactivity. Addition of normal, hypertensive, and uremic plasma to a human renin-sheep renin substrate system inhibited the rate of angiotensin generation, although significantly less inhibition was observed with uremic plasma. The reactivity of renin increased in normal plasma but not in uremic plasma after treatment with 95% acetone. After acetone extraction renin reactivity in normal and plasma inhibited the rate of angiotensin generation in a renin-renin substrate system. Less inhibition occurred with the acetone extract from a pool of uremic plasma. These results provide evidence for the existence of a naturally occurring acetone soluble renin inhibiting factor in normal and uremic plasma. The increased reactivity of renin in uremic plasma may be related to a deficiency of this factor.

Topics: Acetone; Angiotensin II; Angiotensinogen; Humans; Hypertension; In Vitro Techniques; Kinetics; Radioimmunoassay; Renin; Solubility; Time Factors; Uremia

1) To clarify the role of adrenal enucleation on plasma renin activity (PRA), plasma renin substrate (PRS), PRA response to furosemide administration and vacular reaction to renin in adrenal regeneration hypertension (ARH), serial changes of PRA and PRS during adrenal regeneration, PRA response to furosemide administration, and pressor response to exogenous renin in ARH were investigated by comparison with those of intact rats, unilaterally adrenalectomized rats, and unilaterally nephroadrenalectomized rats with contralateral adrenalectomy or with contralateral adrenal exploration (control) on both tap water and high sodium intake. 2) The control rats drinking saline, when compared with intact rats drinking tap water, showed significant decreases in PRA and, concomitantly, significant increases in PRS throughout the experimental period. In the unilaterally nephroadrenalectomized rats drinking saline, two days after adrenal enucleation or adrenalectomy, a significant increase in PRA, with a concomitant decrease in PRS, was observed. Those changes were less pronounced in the adrenal enucleated group than in the adrenalectomized group. Ten days later PRA markedly decreased to the control level in both groups. PRS rose to the control level on the 10th day after adrenal enucleation without increasing further, while that in the adrenalectomized group remained as low as before. 3) No significant differences in any of the experimental groups were found in diuresis, natriuresis, or in changes in body weight and hematocrit during the one and a half hours after furosemide administration performed at the 9th experimental week. The basal PRA was significantly decreased in the other groups with unilateral nephroadrenalectomy and/or a high sodium intake as compared with the unilaterally adrenalectomized rats drinking tap water. The decrease in basal PRA was much more pronounced in the unilaterally nephroadrenalectomized rats drinking saline, with or without adrenal enucleation. After furosemide administration, PRA significantly increased in the unilaterally adrenalectomized rats drinking saline as well as in the unilaterally nephroadrenalectomized rats drinking tap water, with or without adrenal enucleation, while PRA values in three groups were only a half of the unilaterally adrenalectomized rats drinking tap water. An insignificant increase was found in the unilaterally nephroadrenalectomized rats drinking saline, independent of adrenall enucleation. 4) Pressor respo

Topics: Adrenal Glands; Adrenal Medulla; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Female; Furosemide; Hypertension; Kidney; Male; Organ Size; Potassium; Rats; Regeneration; Renin; Sodium; Sodium Chloride

A series of lysophosphatidylethanolamine analogs containing saturated and methylene-interrupted cis-olefinic fatty chains was synthesized by phosphorylation and phosphonylation of respective fatty alcohols. Arachidonyl- and linolenylphosphorylethanolamines (12, 13), arachidonyl (2-phthalimidoethyl)phosphonate (17), and arachidonyl (2-aminoethyl)phosphonate (18) were found to be effective inhibitors of the renin-renin substrate reaction in vitro; lysophosphatidylethanolamine analogs 14-16 of lesser unsaturation were either weakly active or inactive. In a preliminary study, intramuscular administration of 25 mg/kg/day of arachidonyl (2-aminoethyl)phosphonate (18) to the hypertensive rat caused pronounced reduction (50 mm) in blood pressure within 3 days; upon continued dosage (15 mg/kg/day) of 18 for an additional 4 days, plasma renin activity was found to be 16 ng/0.1 ml/15 hr as compared with 69 ng/0.1 ml/15 hr before initial drug administration. Arachidonic acid (3), arachidonyl alcohol (8), and several corresponding tetraenoid ester, amide, mesylate, and glyceryl ether derivatives (4-7, 10, 11), that are not phosphate or phosphonate esters, were found to exhibit negligible or modest inhibition of renin activity in vitro.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Depression, Chemical; Dogs; Hypertension; In Vitro Techniques; Lysophospholipids; Phosphatidylethanolamines; Rats; Renin; Structure-Activity Relationship

Topics: Adolescent; Adult; Age Factors; Aldosterone; Angiotensin II; Angiotensinogen; Body Weight; Contraceptives, Oral; Diuresis; Estrogens; Female; Hemodynamics; Humans; Hypertension; Natriuresis; Pituitary-Adrenal System; Renin; Sodium; Sympathetic Nervous System

Topics: Angiotensinogen; Angiotensins; Blood Pressure Determination; Carbon Tetrachloride; Epinephrine; Fatty Liver; Hypertension; Hypertension, Renal; Kidney; Norepinephrine; Pathology; Pharmacology; Rats; Renin; Research; Toxicology

Hog renin substrate has been separated into three major (A, B, and C) and two minor forms (D and E) by DEAE cellulose chromatography. Two of the major forms (B and C) have been further fractionated into two additional types (1 and 2) by countercurrent distribution. The purification of substrates A, C(1), and C(2) has been completed. Analysis shows that all three are glycoproteins with molecular weights of about 57,000, and have similar amino acid compositions. Differences exist in the sialic acid, glucosamine, and neutral hexose content, which may account for different physical properties. All the forms of the substrates are attacked by renin at similar rates, and appear to yield the same angiotensin I.

Topics: Amino Acids; Angiotensinogen; Enzyme Precursors; Glycoproteins; Hypertension; Molecular Weight; Renin

Topics: Angiotensinogen; Animals; Blood Pressure; Blood Pressure Determination; Hypertension; Hypertension, Renal; Kidney; Rabbits; Renin; Viscera

Topics: Angiotensinogen; Diuresis; Diuretics; Humans; Hypertension; Pepsin A

Topics: Angiotensinogen; Angiotensins; Blood Pressure; Blood Pressure Determination; Humans; Hypertension; Renin

Topics: Angiotensin Amide; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Blood Pressure Determination; Dogs; Hypertension; Kidneys, Artificial; Renal Dialysis

Topics: Angiotensinogen; Angiotensins; Blood Pressure; Blood Pressure Determination; Humans; Hypertension; Kidney

Topics: Angiotensin Amide; Angiotensinogen; Angiotensins; Blood Pressure; Humans; Hypertension; Hypertension, Renal; Kidney

Topics: Adrenal Glands; Angiotensinogen; Angiotensins; Epinephrine; Hypertension; Tissue Extracts; Tyrosine