angiotensinogen and Inflammation

Corona virus disease-19 (covid-19) is caused by a coronavirus that is also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and is generally characterized by fever, respiratory inflammation, and multi-organ failure in susceptible hosts. One of the first things during inflammation is the response by acute phase proteins coupled with coagulation. The angiotensinogen (a substrate for hypertension) is one such acute phase protein and goes on to explain an association of covid-19 with that of angiotensin-converting enzyme-2 (ACE2, a metallopeptidase). Therefore, it is advisable to administer, and test the efficacy of specific blocker(s) of angiotensinogen such as siRNAs or antibodies to covid-19 subjects. Covid-19 activates neutrophils, macrophages, but decreases T-helper cells activity. The metalloproteinases promote the activation of these inflammatory immune cells, therefore; we surmise that doxycycline (a metalloproteinase inhibitor, and a safer antibiotic) would benefit the covid-19 subjects. Along these lines, an anti-acid has also been suggested for mitigation of the covid-19 complications. Interestingly, there are three primary vegetables (celery, carrot, and long-squash) which are alkaline in their pH-range as compared to many others. Hence, treatment with fresh juice (without any preservative) from these vegies or the antioxidants derived from purple carrot and cabbage together with appropriate anti-coagulants may also help prevent or lessen the detrimental effects of the covid-19 pathological outcomes. These suggested remedies might be included in the list of putative interventions that are currently being investigated towards mitigating the multi-organ damage by Covid-19 during the ongoing pandemic.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; COVID-19; COVID-19 Drug Treatment; Heart; Heart Failure; Humans; Inflammation; Neutrophils; Pandemics; RNA, Small Interfering; SARS-CoV-2

Excess adiposity can induce adverse sequelae in multiple cell types and organ systems. The transition from the lean to the obese state is characterized by fundamental cellular changes at the level of the adipocyte. These changes affect the local microenvironment within the respective adipose tissue but can also affect nonadipose systems. Adipocytes within fat pads respond to chronic nutrient excess through hyperplasia or hypertrophy, which can differentially affect interorgan crosstalk between various adipose depots and other organs. This crosstalk is dependent on the unique ability of the adipocyte to coordinate metabolic adjustments throughout the body and to integrate responses to maintain metabolic homeostasis. These actions occur through the release of free fatty acids and metabolites during times of energy need - a process that is altered in the obese state. In addition, adipocytes release a wide array of signalling molecules, such as sphingolipids, as well as inflammatory and hormonal factors (adipokines) that are critical for interorgan crosstalk. The interactions of adipose tissue with the kidney - referred to as the adipo-renal axis - are important for normal kidney function as well as the response of the kidney to injury. Here, we discuss the mechanistic basis of this interorgan crosstalk, which clearly has great therapeutic potential given the increasing rates of chronic kidney disease secondary to obesity and type 2 diabetes mellitus.

Topics: Adipokines; Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Angiotensin II; Angiotensinogen; Ceramidases; Diabetes Mellitus, Type 2; Humans; Inflammation; Kidney Diseases; Leptin; Macrophages; Obesity; Receptors, Adiponectin; Signal Transduction

Pro-coagulant, anti-coagulant and fibrinolytic pathways are responsible for maintaining hemostatic balance under physiological conditions. Any deviation from these pathways would result in hypercoagulability leading to life threatening diseases like myocardial infarction, stroke, portal vein thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE). Angiogenesis is the process of sprouting of new blood vessels from pre-existing ones and plays a critical role in vascular repair, diabetic retinopathy, chronic inflammation and cancer progression. Serpins; a superfamily of protease inhibitors, play a key role in regulating both angiogenesis and coagulation. They are characterized by the presence of highly conserved secondary structure comprising of 3 β-sheets and 7-9 α-helices. Inhibitory role of serpins is modulated by binding to cofactors, specially heparin and heparan sulfate proteoglycans (HSPGs) present on cell surfaces and extracellular matrix. Heparin and HSPGs are the mainstay of anti-coagulant therapy and also have therapeutic potential as anti-angiogenic inhibitors. Many of the heparin binding serpins that regulate coagulation cascade are also potent inhibitors of angiogenesis. Understanding the molecular mechanism of the switch between their specific anti-coagulant and anti-angiogenic role during inflammation, stress and regular hemostasis is important. In this review, we have tried to integrate the role of different serpins, their interaction with cofactors and their interplay in regulating coagulation and angiogenesis.

Topics: Angiotensinogen; Animals; Anticoagulants; Antithrombins; Blood Coagulation; Blood Proteins; Blood Vessels; Disease Progression; Extracellular Matrix; Eye Proteins; Fibrinolysis; Heparan Sulfate Proteoglycans; Heparin; Heparin, Low-Molecular-Weight; Homeostasis; Humans; Inflammation; Molecular Conformation; Neovascularization, Pathologic; Nerve Growth Factors; Plasminogen Activator Inhibitor 1; Protein C Inhibitor; Serpin E2; Serpins; Signal Transduction

Elevated blood glucose, obesity, high blood pressure, elevated triglycerides and low high density lipoprotein (HDL) cholesterol are well accepted risk factors in the development of coronary artery disease. Clustering of at least three of these factors in an individual is defined as metabolic syndrome (MetS). Obesity is a central pathological mechanism in the disease and it is expected that the incidence of this condition will increase dramatically within the next years. The visceral adipose tissue is not only an energy depot but also an endocrine organ which produces a large number of bioactive molecules, the so called adipokines. In the setting of obesity, the over-production of proinflammatory and pro-thrombotic adipokines is associated with insulin resistance. This mechanism represents the pathophysiological basis for the development of MetS. Inflammation has a central role in the pathogenesis of MetS and in mediating its impact on the development of cardiovascular disease. Knowledge of these mechanisms has relevance in the context of preventive and therapeutic strategies.

Topics: Adiponectin; Adolescent; Adult; Angiotensinogen; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Chemokine CCL2; Endothelium, Vascular; Humans; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Plaque, Atherosclerotic; Plasminogen Activator Inhibitor 1; Prognosis; Resistin; Risk; Tumor Necrosis Factor-alpha

Obesity is a worldwide pandemic that causes a multitude of co-morbid conditions.However, there has been slow progress in understanding the basic pathophysiology that underlies co-morbid conditions associated with obesity. Recently, there has been intense interest in the role of inflammation in obesity. Using the inflammatory hypothesis, many of the mechanisms by which co-morbid conditions are associated with obesity are being elucidated.. We searched the literature and reviewed all relevant articles. We focused on hormones and cytokines that have been associated with other inflammatory conditions such as sepsis and systemic inflammatory response syndrome.. Angiotensinogen (AGT), transforming growth factor beta (TGFbeta), tumor necrosis factor alpha (TNFalpha), and interleukin six (IL-6) are all elevated in obesity and correlate with several markers of adipocyte mass. These mediators have detrimental effects on hypertension, diabetes, dyslipidemia, thromboembolic phenomena, infections, and cancer. Weight loss results in a reduction of inflammatory mediators and a diminution of the associated co-morbid conditions.. The success of weight loss surgery in treating the complications associated with obesity is most probably related to the reduction of inflammatory mediators. While some aspects of bariatric physiology remain unclear, there appears to be a strong association between obesity and inflammation, thereby rendering obesity a chronic inflammatory state. A clearer understanding of the physiology of obesity will allow physicians who treat the obese to develop better strategies to promote weight loss and improve the well-being of millions of individuals.

Topics: Acute-Phase Proteins; Adipose Tissue; Angiotensin II; Angiotensinogen; C-Reactive Protein; Humans; Inflammation; Insulin Resistance; Interleukin-6; Liver; Lymphotoxin-alpha; Morbidity; Obesity; Tumor Necrosis Factor-alpha; Weight Loss

The adipose renin-angiotensin system (RAS) has been linked to obesity-induced inflammation, though mechanisms are not completely understood. In this study, adipose-specific angiotensinogen knockout mice (Agt-KO) were generated to determine whether Agt inactivation reduces inflammation and alters the metabolic profile of the Agt-KO mice compared to wild-type (WT) littermates.. Adipose tissue-specific Agt-KO mice were created using the Cre-LoxP system with both Agt-KO and WT littermates fed either a low-fat or high-fat diet to assess metabolic changes. White adipose tissue was used for gene/protein expression analyses and WAT stromal vascular cells for metabolic extracellular flux assays.. No significant differences were observed in body weight or fat mass between both genotypes on either diet. However, improved glucose clearance was observed in Agt-KO compared to WT littermates, consistent with higher expression of genes involved in insulin signaling, glucose transport, and fatty acid metabolism. Furthermore, Agt inactivation reduced total macrophage infiltration in Agt-KO mice fed both diets. Lastly, stroma vascular cells from Agt-KO mice revealed higher metabolic activity compared to WT mice.. These findings indicate that adipose-specific Agt inactivation leads to reduced adipose inflammation and increased glucose tolerance mediated in part via increased metabolic activity of adipose cells.

Topics: Adipose Tissue; Adipose Tissue, White; Angiotensinogen; Animals; Inflammation; Macrophages; Mice; Mice, Knockout

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

To investigate the effects of vitamin D and its receptor on cytokines expression and podocytes apoptosis.. Cultured mouse podocytes were pre-incubated with vitamin D or transiently transfected with small interfering ribonucleic acid (RNA) to knock down the vitamin D receptor. Lipopolysaccharide was used to mimic the inflammation status of diabetes.. In a lipopolysaccharide-induced state, expressions of transforming growth factor-β, angiotensinogen and vascular endothelial growth factor were similarly increased. Transforming growth factor-β and angiotensinogen levels originally elevated by lipopolysaccharide challenge were distinctly reduced after pre-incubation with vitamin D. Whereas after vitamin D receptor small interfering (si)RNA transfection, the aforementioned cytokines had opposite changes as expected. However, neither vitamin D pretreatment nor vitamin D receptor siRNA transfection influenced the previously increased vascular endothelial growth factor expression at messenger RNA or protein levels. When pretreated with vitamin D, decreases were observed for phosphorylated inhibitor-κB and the inhibitor kinase proteins. After siRNA transfection, those proteins levels were further elevated. The originally increased transforming growth factor-β and angiotensinogen levels as a result of lipopolysaccharide stimulation were reduced at both the messenger RNA and protein levels after the specific inhibition of the nuclear factor-κB pathway with pyrrolidine dithiocarbamate. The apoptosis rate of podocytes was decreased in a parallel manner after vitamin D pre-incubation, and increased after siRNA transfection, which was also suppressed by pyrrolidine dithiocarbamate.. Vitamin D and its receptor might be involved in the progression of diabetic nephropathy by regulating transforming growth factor-β, angiotensinogen expression and apoptosis of podocytes. The processes are mediated through the signaling of nuclear factor-κB pathway.

Topics: Angiotensinogen; Animals; Apoptosis; Cells, Cultured; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Podocytes; Receptors, Calcitriol; Signal Transduction; Transforming Growth Factor beta; Vitamin D

Topics: Angiotensinogen; Heart Failure, Diastolic; Humans; Inflammation; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

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

Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Captopril; Glucose Intolerance; Glycerolphosphate Dehydrogenase; Inflammation; Insulin Resistance; Interleukin-10; Male; Mice; Muscle, Skeletal; NF-kappa B; Obesity; Up-Regulation

We previously reported that adenosine monophosphate-activated protein kinase (AMPK) activity is lower in adipose tissue of morbidly obese individuals who are insulin resistant than in comparably obese people who are insulin sensitive. However, the number of patients and parameters studied were small. Here, we compared abdominal subcutaneous, epiploic, and omental fat from 16 morbidly obese individuals classified as insulin sensitive or insulin resistant based on the homeostatic model assessment of insulin resistance. We confirmed that AMPK activity is diminished in the insulin resistant group. A custom PCR array revealed increases in mRNA levels of a wide variety of genes associated with inflammation and decreases in PGC-1α and Nampt in omental fat of the insulin resistant group. In contrast, subcutaneous abdominal fat of the same patients showed increases in PTP-1b, VEGFa, IFNγ, PAI-1, and NOS-2 not observed in omental fat. Only angiotensinogen and CD4(+) mRNA levels were increased in both depots. Surprisingly, TNFα was only increased in epiploic fat, which otherwise showed very few changes. Protein carbonyl levels, a measure of oxidative stress, were increased in all depots. Thus, adipose tissues of markedly obese insulin resistant individuals uniformly show decreased AMPK activity and increased oxidative stress compared with insulin sensitive patients. However, most changes in gene expression appear to be depot-specific.

Topics: Adenylate Kinase; Adipose Tissue; Adult; Angiotensinogen; Body Mass Index; Enzyme Activation; Female; Gene Expression Regulation, Enzymologic; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Oxidative Stress; Phosphorylation; RNA, Messenger; Tumor Necrosis Factor-alpha

Excessive secretion of proinflammatory adipokines has been linked to metabolic disorders. We have previously documented anti-inflammatory effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) in adipose tissue; however, the mechanisms by which these fatty acids regulate adipokine secretion remain unclear. Here, we determined differential effects of eicosapentaenoic acid (EPA, n-3 PUFA) vs. arachidonic acid (AA, n-6 PUFA) on expression and secretion of angiotensinogen (Agt), interleukin 6 (IL-6) and monocyte chemotactic protein (MCP-1) in 3T3-L1 adipocytes. While both PUFAs increased intracellular Agt protein and mRNA expression, Agt secretion into culture media was increased only by AA treatment, which in turn was prevented by co-treatment with EPA. At various AA/EPA ratios, increasing AA concentrations significantly increased secretion of the above three adipokines, whereas increasing EPA dose-dependently, while lowering AA, decreased their secretion. Moreover, IL-6 and MCP-1 were more significantly reduced by EPA treatment compared to Agt (IL-6>MCP>Agt). Next, we tested whether nuclear factor-κB (NF-κB), a major proinflammatory transcription factor, was involved in regulation of these adipokines by PUFAs. EPA significantly inhibited NF-κB activation compared to control or AA treatments. Moreover, EPA attenuated tumor necrosis factor-α-induced MCP-1 and further reduced its secretion in the presence of an NF-κB inhibitor. Taken together, we reported here novel beneficial effects of EPA in adipocytes. We demonstrated direct anti-inflammatory effects of EPA, which are at least in part due to the inhibitory effects of this n-3 PUFA on the NF-κB pathway in adipocytes. In conclusion, these studies further support beneficial effects of n-3 PUFAs in adipocyte inflammation and metabolic disorders.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Adipose Tissue; Angiotensinogen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cell Differentiation; Chemokine CCL2; Diet, High-Fat; Eicosapentaenoic Acid; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; NF-kappa B

The aim of the present study was to map the distribution of representative protein components of the renin-angiotensin system (RAS) in the human gastric mucosa.. Biopsies from the antral and corporal mucosa of healthy Helicobacter pylori negative and positive volunteers were assessed by histology, Western blot and immunohistochemistry for angiotensin II subtype 1 and 2 receptors (AT1R, AT2R) and other RAS components (angiotensinogen, renin, angiotensin converting enzyme, and neprilysin). Mucosal levels of myeloperoxidase (MPO) served as a protein marker of neutrophil infiltration.. AT1R and AT2R were located in a variety of cells in the human gastric mucosa, including AT1R on a subpopulation of endocrine cells in the antral mucosa. Angiotensinogen and renin were expressed by resident mesenchymal cells in lamina propria. All investigated RAS components were found in vascular endothelial cells. The AT1R protein expression was 3-4 times higher in the gastric mucosa of H. pylori positive subjects compared to the gastric mucosa of H. pylori negative subjects (p < 0.05). Gastric mucosal AT1R protein expression correlated positively with neutrophil infiltration (r = 0.7, p < 0.05).. Protein components of RAS are present in the human gastric mucosa. The results suggest an angiotensin II mediated impact on mucosal epithelial functions, antral endocrine properties, microvascular permeability, and gastric inflammation.

Topics: Adult; Aged; Angiotensinogen; Female; Gastric Mucosa; Helicobacter pylori; Humans; Inflammation; Male; Middle Aged; Neprilysin; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Young Adult

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

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

Aldosterone and angiotensin (Ang) II both may cause organ damage. Circulating aldosterone is produced in the adrenals; however, local cardiac synthesis has been reported. Aldosterone concentrations depend on the activity of aldosterone synthase (CYP11B2). We tested the hypothesis that reducing aldosterone by inhibiting CYP11B2 or by adrenalectomy (ADX) may ameliorate organ damage. Furthermore, we investigated how much local cardiac aldosterone originates from the adrenal gland.. We investigated the effect of the CYP11B2 inhibitor FAD286, losartan, and the consequences of ADX in transgenic rats overexpressing both the human renin and angiotensinogen genes (dTGR). dTGR-ADX received dexamethasone and 1% salt. Dexamethasone-treated dTGR-salt served as a control group in the ADX protocol. Untreated dTGR developed hypertension and cardiac and renal damage and had a 40% mortality rate (5/13) at 7 weeks. FAD286 reduced mortality to 10% (1/10) and ameliorated cardiac hypertrophy, albuminuria, cell infiltration, and matrix deposition in the heart and kidney. FAD286 had no effect on blood pressure at weeks 5 and 6 but slightly reduced blood pressure at week 7 (177+/-6 mm Hg in dTGR+FAD286 and 200+/-5 mm Hg in dTGR). Losartan normalized blood pressure during the entire study. Circulating and cardiac aldosterone levels were reduced in FAD286 or losartan-treated dTGR. ADX combined with dexamethasone and salt treatment decreased circulating and cardiac aldosterone to barely detectable levels. At week 7, ADX-dTGR-dexamethasone-salt had a 22% mortality rate compared with 73% in dTGR-dexamethasone-salt. Both groups were similarly hypertensive (190+/-9 and 187+/-4 mm Hg). In contrast, cardiac hypertrophy index, albuminuria, cell infiltration, and matrix deposition were significantly reduced after ADX (P<0.05).. Aldosterone plays a key role in the pathogenesis of Ang II-induced organ damage. Both FAD286 and ADX reduced circulating and cardiac aldosterone levels. The present results show that aldosterone produced in the adrenals is the main source of cardiac aldosterone.

Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Cytochrome P-450 CYP11B2; Enzyme Inhibitors; Fibrosis; Heart Diseases; Humans; Inflammation; Kidney Diseases; Losartan; Mineralocorticoid Receptor Antagonists; Myocardium; Rats; Renin

To investigate whether an inflammatory response occurs in patients undergoing infrarenal aortic abdominal aneurysm repair, the localization and timing (ischemia and/or reperfusion) of this activation, and finally whether it affects postoperative pulmonary function.. Prospective, observational study.. Academic referral center in Italy.. We included 12 patients undergoing infrarenal aortic abdominal aneurysm repair and 12 patients undergoing major abdominal surgery.. Timed measurement of gene activation (angiotensinogen, angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6 genes) in muscle biopsies by reverse transcriptase-polymerase chain reaction (RT-PCR), and prospective assessment of interleukin-6 plasma concentration and pulmonary function (Pao2/FIO2 and Pao2/PAO2 ratios).. After 30 mins of aortic clamping, angiotensinogen, angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6 genes were all overexpressed at RT-PCR studies in quadriceps muscle of patients undergoing aortic abdominal aneurysm repair, and the overexpression persisted after reperfusion. In situ hybridization and immunohistochemistry revealed that the inflammatory response was localized in endothelial cells. A significant increase in plasma interleukin-6 concentrations was then detectable at 6 and 12 hrs after reperfusion in aortic abdominal aneurysm surgery compared with patients undergoing abdominal surgery (p < .05). The increase in interleukin-6 plasma concentration was then followed (12 and 24 hrs after surgery) by a significant reduction of Pao2/ FIO2 and Pao2/PAO2 ratios (p < .05 vs. abdominal surgery).. The present study shows that a) during aortic surgery, the genes for interleukin-6 and for the components of the local renin-angiotensin system (angiotensinogen, angiotensin-converting enzyme, and angiotensin type 1 receptor subtype) are activated early in the ischemic muscle, and activation persists during reperfusion; b) interleukin-6 plasma concentration increases only in patients with tissue ischemia (aortic abdominal aneurysm), whereas no changes are detectable in patients with abdominal surgery; and finally c) the occurrence of systemic inflammatory reaction with increased interleukin-6 plasma concentrations is followed by impaired pulmonary function.

Topics: Aged; Angiotensinogen; Aortic Aneurysm, Abdominal; Colectomy; Female; Gastrectomy; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Lung Diseases; Male; Middle Aged; Muscle, Skeletal; Nephrectomy; Peptidyl-Dipeptidase A; Postoperative Complications; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reperfusion Injury; Systemic Inflammatory Response Syndrome; Thigh; Transcriptional Activation; Treatment Outcome

Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antigens, CD; B7-2 Antigen; Blood Pressure; Dendritic Cells; Dexamethasone; Etanercept; Histocompatibility Antigens Class II; Humans; Immunoglobulin G; Immunosuppressive Agents; Inflammation; Kidney; Kidney Diseases; Kinetics; Macrophage Migration-Inhibitory Factors; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mycophenolic Acid; NADPH Dehydrogenase; NADPH Oxidases; NF-kappa B; Phosphoproteins; Protective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Tumor Necrosis Factor; Renin; T-Lymphocytes

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. The relative order of potency in releasing angiotensin II by the three proteinases at equivalent concentrations is cathepsin G > elastase > proteinase 3. When all three proteinases are used together, the release of angiotensin II is greater than the sum of the release when each proteinase is used individually. Cathepsin G and elastase can also degrade angiotensin II, reactions which might be important in regulating the activity of angiotensin II. The release and degradation of angiotensin II by the neutrophil proteinases are reactions which could play a role in the local inflammatory response and wound healing.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Binding Sites; Cathepsin G; Cathepsins; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Humans; Inflammation; Models, Biological; Myeloblastin; Neutrophils; Pancreatic Elastase; Protein Binding; Serine Endopeptidases; Time Factors; Wound Healing

Reports on the effectiveness of endothelin receptor blockers in angiotensin (Ang) II-induced end-organ damage are conflicting, and the mechanisms involved are uncertain. We tested the hypothesis that endothelin (ET)(A/B) receptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) ameliorates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidated the effect of bosentan on tissue factor (TF), which is a key regulator of the extrinsic coagulation cascade. We compared bosentan with hydralazine (80 mg/L in the drinking water for 3 weeks) as a blood pressure control. Untreated dTGR featured hypertension, focal necrosis in heart and kidney, and a 45% mortality rate (9 of 20) at age 7 weeks. Compared with Sprague-Dawley controls, both systolic blood pressure and 24-hour albuminuria were increased in untreated dTGR (203+/-8 versus 111+/-2 mm Hg and 67.1+/-8.6 versus 0.3+/-0.06 mg/d at week 7, respectively). Bosentan and hydralazine both reduced blood pressure and cardiac hypertrophy. Mortality rate was markedly reduced by bosentan (1/15) and partially by hydralazine (4/15). However, only bosentan decreased albuminuria and renal injury. Untreated and hydralazine-treated dTGR showed increased nuclear factor (NF)-kappaB and AP-1 expression in the kidney and heart; the p65 NF-kappaB subunit was increased in the endothelium, vascular smooth muscles cells, infiltrating cells, glomeruli, and tubules. In the heart and kidney, ET(A/B) receptor blockade inhibited NF-kappaB and AP-1 activation compared with hydralazine treatment. Macrophage infiltration, ICAM-1 expression, and the integrin expression on infiltrating cells were markedly reduced. Renal vasculopathy was accompanied by increased tissue factor expression on macrophages and vessels of untreated and hydralazine-treated dTGR, which was markedly reduced by bosentan. Thus, ET(A/B) receptor blockade inhibits NF-kappaB and AP-1 activation and the NF-kappaB- and/or AP-1-regulated genes ICAM-1, VCAM-1, and TF, independent of blood pressure-related effects. We conclude that Ang II-induced NF-kappaB and AP-1 activation and subsequent inflammation and coagulation involve at least in part the ET(A/B) receptors.

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiomegaly; Fibronectins; Heart; Humans; Hydralazine; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Kidney; Macrophages; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Renin; Sulfonamides; Thromboplastin; Transcription Factor AP-1; Vascular Cell Adhesion Molecule-1

This study focused on the association between plaque psoriasis and polymorphisms of several inflammation genes. Included in the study were 142 Caucasian (Czech) patients with plaque psoriasis and 141 healthy subjects. The genotypes of the polymorphisms in angiotensinogen [M235T ATG, A(-6)G ATG], in transporters associated with antigen processing TAP1 (TAP1*0101, TAP*02011 and TAP1*0301) and in lymphotoxin alpha (TNFbeta) (NcoI in intron 1) were detected by polymerase chain reaction-based methods and restriction enzyme analysis. An increase in B1 (less frequent) allele of NcoI TNFbeta polymorphism was found in psoriatic patients compared to healthy individuals (odds ratio = 1.6, 95% confidence interval 1.13-2.26, P = 0.006). A positive family history of psoriasis was associated with a higher B1 allele frequency in NcoI TNFbeta (P = 0.011). Hardy-Weinberg disequilibrium was found in TAP1 polymorphism A-->G at nucleotide 1207 in psoriatic patients. A case-control difference was found in the allelic concurrence of M235T and A(-6)G ATG polymorphisms. The most frequent population genotypes MMGG, MTAG and TTAA were observed in 92% of patients vs 74% of control subjects (odds ratio 0.29, 95% confidence interval 0.14-0.60, P = 0.0003). A positive history of tonsillitis and/or tonsillectomy was associated with a higher T allele frequency of the M235T ATG polymorphism (P = 0.037) as well as with a higher G allele frequency of the A(-6)G ATG polymorphism (P = 0.022). Polymorphisms in proinflammatory angiotensinogen and TNFbeta genes were associated with plaque psoriasis, a positive family history of psoriasis and with frequent tonsillitis in childhood.

Topics: Adult; Alleles; Angiotensinogen; ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP-Binding Cassette Transporters; Case-Control Studies; DNA; Female; Gene Frequency; Genotype; Humans; Inflammation; Lymphotoxin-alpha; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Psoriasis; Sequence Analysis, DNA

Angiotensinogen has been assumed to be an acute-phase protein, because some forms of acute inflammation, eg, the injection of lipopolysaccharide or cellite or partial hepatectomy, increased the hepatic synthesis of angiotensinogen. In addition, the well-characterized nephrectomy-induced stimulation of angiotensinogen was thought to represent an acute-phase reaction. To evaluate this hypothesis, we examined changes in angiotensinogen secretion by the isolated perfused rat liver after the systemic administration of turpentine or lipopolysaccharide as well as in response to nephrectomy or sham nephrectomy. Comparison was made with the secretion of two typical acute-phase proteins, alpha 1-acid glycoprotein and alpha 2-macroglobulin, and with the secretion of the negative acute-phase protein albumin. All forms of experimental surgery stimulated the secretion of both control acute-phase proteins several-fold. In contrast, the response of angiotensinogen was not uniform; lipopolysaccharide and bilateral nephrectomy stimulated secretion twofold to threefold, sham nephrectomy had no effect, and turpentine decreased the secretion to 30% of the control level. A similar inhomogeneity was found in an additional experiment performed to analyze the direct effects of interleukin-1 or interleukin-6 on the secretion of angiotensinogen by freshly isolated hepatocytes. Interleukin-6 increased but interleukin-1 decreased the mRNA and secretion of angiotensinogen, whereas both cytokines increased the secretion of both acute-phase proteins. Because of this nonuniform behavior of angiotensinogen, it is premature to classify angiotensinogen as an acute-phase protein until a specific function for angiotensinogen during acute inflammation is known.

Topics: Acute-Phase Proteins; Angiotensinogen; Animals; Cells, Cultured; Escherichia coli; Inflammation; Interleukin-1; Interleukin-6; Lipopolysaccharides; Liver; Male; Nephrectomy; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Serum Albumin; Turpentine

Angiotensinogen is thought to be an acute-phase protein, since its plasma concentrations increase in response to some inflammatory conditions, e.g. partial hepatectomy, nephrectomy or lipopolysaccharide (LPS) injection. However, this response of angiotensinogen has never been related to that of established acute-phase proteins. We have, therefore, examined plasma concentrations and hepatic secretion of angiotensinogen in two widely used inflammation models, i.e. turpentine or LPS injection in the rat, as well as in nephrectomized and sham-nephrectomized rats, in comparison to the response of two established acute-phase proteins, alpha 1-acid glycoprotein (AGP) and alpha 2-macroglobulin (AMG). Plasma concentrations and secretion rates of AGP and AMG increased significantly in all the conditions examined. The magnitude of the response decreased in the order turpentine > nephrectomy = LPS > sham nephrectomy. Angiotensinogen secretion was stimulated in LPS-injected (2.5-fold) and nephrectomized rats (2.6-fold), whereas no changes were seen in sham-nephrectomized rats. Surprisingly, a significant decrease both in secretion rates and plasma concentrations of angiotensinogen occurred in turpentine-injected rats. Intraperitoneal injection of interleukin 6, a major inductor of hepatic acute-phase proteins, increased plasma concentrations and hepatic secretion rates of AGP, AMG and angiotensinogen. Changes in liver angiotensinogen mRNA correlated well with angiotensinogen secretion rates in all groups, indicating that alterations in angiotensinogen synthesis are responsible for the observed changes in secretion rates and plasma concentrations. The response of angiotensinogen to turpentine is difficult to reconcile with the conventional definition of an acute-phase protein.

Topics: alpha-Macroglobulins; Angiotensinogen; Animals; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Inflammation; Injections, Intraperitoneal; Interleukin-6; Lipopolysaccharides; Liver; Male; Nephrectomy; Orosomucoid; Rats; Rats, Sprague-Dawley; Renin; Turpentine

The concentration of plasma angiotensinogen increases upon induction of inflammation. Studies were carried out using serum samples collected from mice and rats after injection of lipopolysaccharide (LPS) to determine whether interleukin-6 (IL-6) is a mediator responsible for the inflammation-induced increase of angiotensinogen synthesis in liver cells. Serum collected from mice or rats 2 and 4 hr after injection of LPS contained a factor that stimulated [35S]methionine incorporation into angiotensinogen newly synthesized by rat hepatoma H4IIEC3 (H4) cells. Assay of IL-6 using an IL-6-dependent murine hybridoma, MH60.BSF2 cells, showed the presence of IL-6-like activity in sera of mice or rats 2 and 4 hr after injection of LPS. Anti-mouse IL-6 monoclonal antibody completely inhibited not only the IL-6-like activity present in LPS-treated mouse serum but also the ability of the serum to stimulate angiotensinogen synthesis of H4 cells. These results suggest that increased synthesis of angiotensinogen in the liver after induction of inflammation is mediated by IL-6, a cytokine important in immune reactions and the hepatic acute-phase response.

Topics: Angiotensinogen; Animals; Antibodies; Blood; Inflammation; Interleukin-6; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred ICR; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured

It has been proposed that angiotensinogen is an acute phase protein, because its plasma concentrations increase during some forms of acute inflammation. However, this is not a consistent finding. Furthermore, no specific function of circulating angiotensinogen in the inflammatory reaction is known. This may be different for extrahepatic synthesis of angiotensinogen, as the local generation of angiotensin II has been implicated in inflammation-related processes in some organs. We have therefore examined the expression of the angiotensinogen gene in liver and extrahepatic tissues under the influence of experimental inflammatory stimuli in comparison to the effects of dexamethasone. Dexamethasone (7 mg/kg intraperitoneally) induced a several-fold increase in angiotensinogen mRNA in liver, aorta, heart, adrenal, and a moderate increase in kidney, testis, and brain. Plasma concentrations of angiotensinogen, alpha 1-acid glycoprotein, and alpha 2-macroglobulin increased, whereas albumin concentrations decreased. Lipopolysaccharide (500 micrograms/kg subcutaneously) stimulated angiotensinogen mRNA in hepatic, cardiac, renal, adrenal, and testicular tissues, but not in the brain. Plasma concentrations of angiotensinogen, alpha 1-acid glycoprotein, and alpha 2-macroglobulin increased, those of albumin decreased. In turpentine-treated rats (5 ml/kg subcutaneously), angiotensinogen mRNA was reduced in liver and kidney; stimulated in adrenals, testis, and heart; and not influenced in the brain. Plasma concentrations of the acute phase proteins increased, whereas angiotensinogen and albumin decreased. It is concluded that hepatic and extrahepatic angiotensinogen gene expression seem to be regulated similarly by dexamethasone and lipopolysaccharide. The different response to turpentine may reflect differences in the pattern of cytokines induced by turpentine or be associated with additional pharmacological effects of turpentine or its metabolites.

Topics: Angiotensinogen; Animals; Blotting, Northern; Dexamethasone; Inflammation; Lipopolysaccharides; Male; Osmolar Concentration; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tissue Distribution; Turpentine

Topics: Angiotensinogen; Animals; Hypertension; Inflammation; Rats

The rat angiotensinogen gene is induced in the course of the hepatic acute-phase response. We demonstrate that monocyte conditioned medium can stimulate transcription of a stably introduced reporter construct driven by 615 base pairs of the angiotensinogen 5'-flanking sequence, as well as the endogenous gene, in Reuber H35 cells. Point mutations of a cis-acting element, located 545 base pairs from the transcription start site and sharing sequence identity with known nuclear factor kappa B (NF kappa B)-binding sites, led to loss of cytokine inducibility. When cloned upstream of a minimal promoter, this cis-acting element imparted transcriptional inducibility by monocyte conditioned medium, interleukin-1, and tumor necrosis factor on a luciferase reporter gene in HepG2 cells. Two distinct proteins bound this element in vitro: a heat-stable, constitutively present, hepatic nuclear protein that gave rise to a DNase I-protected footprint covering the functionally defined element; and a binding protein of different mobility, induced by monocyte conditioned medium, which also recognized the NF kappa B-binding site of the murine kappa light-chain enhancer. UV cross-linking showed this inducible protein to have an apparent molecular mass of 50 kilodaltons, similar to that described for NF kappa B and distinct from the constitutively present protein that was shown by Southwestern (DNA-protein) blot to have a molecular mass of 32 kilodaltons. Methylation interference analysis showed that the induced species made contact points with guanine residues in the NF kappa B consensus sequence typical of NF kappa B. Induction of this binding activity did not require new protein synthesis, and 12-O-tetradecanoylphorbol-13-acetate could mimic the induction by cytokines. We thus provide direct evidence for involvement of NF kappa B or a similar factor in the hepatic acute-phase response and discuss the potential role of the presence of a constitutive nuclear factor binding the same cis element.

Topics: Acute-Phase Reaction; Angiotensinogen; Animals; Base Sequence; Cycloheximide; DNA Mutational Analysis; DNA-Binding Proteins; Gene Expression Regulation, Enzymologic; Genes; In Vitro Techniques; Inflammation; Lipopolysaccharides; Molecular Sequence Data; Molecular Weight; Nuclear Proteins; Rats; Regulatory Sequences, Nucleic Acid; Tetradecanoylphorbol Acetate; Transcription Factors; Transcription, Genetic

The plasma level of angiotensinogen during the chronic phase of inflammation was studied for comparison with those of other acute-phase reactants in rat adjuvant arthritis. In response to a single injection of Freund's complete adjuvant, this level exhibited a transient increase during the first 24 h. By contrast, increased levels of plasma T-kininogen and alpha 2-macroglobulin, typical acute-phase reactions in the rat, were maintained during the 4-week experimental period. These results suggest that the hepatic synthesis of angiotensinogen is stimulated only in the early phase of chronic inflammation, and therefore that the mechanism underlying the acute-phase response of angiotensinogen is distinct from those currently suggested for other acute-phase reactants.

Topics: Acute-Phase Reaction; alpha-Macroglobulins; Angiotensinogen; Animals; Arthritis; Arthritis, Experimental; Chronic Disease; Corticosterone; Inflammation; Kininogens; Male; Rats

Angiotensinogen is the precursor of biologically active peptide angiotensin II and its hepatic synthesis is increased by the induction of acute inflammation. Studies were carried out to know whether the rise in plasma angiotensinogen is actually involved in the activity of the renin-angiotensin system during acute inflammation. The plasma level of angiotensinogen in rats was increased to 2.5 times the normal level 16 h after the induction of acute inflammation by administration of lipopolysaccharide (LPS). The plasma renin concentration (PRC) was decreased to about 40% of the normal level concomitantly with a reduction of plasma renin activity (PRA) at 4 h after LPS administration. In contrast, 16 h after LPS injection, when plasma angiotensinogen showed a high level and PRC had recovered to the normal range, PRA was increased to 1.7 times the normal level. These results indicate that acute inflammation induced by LPS causes a biphasic change in the generation of angiotensin I, i.e., an early decrease depending upon the reduction of PRC and later increase depending upon elevation of the angiotensinogen concentration.

Topics: Acute Disease; Angiotensin I; Angiotensinogen; Animals; Inflammation; Lipopolysaccharides; Male; Rats; Rats, Inbred F344; Renin; Renin-Angiotensin System

The effect of different experimental models of inflammation on plasma concentrations of T-kininogen and angiotensinogen was examined in the rat. T-kininogen, a major phase protein which inhibits cysteine proteinase is increased in all cases of induced inflammation: administration of lipopolysaccharide and turpentine, bilateral nephrectomy or sham-operation and intraperitoneal injection of peanut oil. Angiotensinogen, the renin-substrate, is increased by lipopolysaccharide but is decreased by turpentine. Sham-operation or peanut oil injection have no effect on angiotensinogen whereas, bilateral nephrectomy and dexamethasone increase its concentration. Therefore, angiotensinogen is regulated differently than T-kininogen during inflammation.

Topics: Angiotensinogen; Animals; Dexamethasone; Inflammation; Kininogens; Lipopolysaccharides; Male; Nephrectomy; Rats; Rats, Inbred Strains; Renin; Turpentine

Acute phase responses of plasma angiotensinogen and kininogen were studied in rats. Plasma angiotensinogen levels increased about 3-fold during the first 8 hr, and returned to normal at 48 hr, following the induction of acute inflammation by lipopolysaccharide (LPS). Plasma kininogen reached maximum levels at 48 hr following LPS administration. In adrenalectomized rats, plasma angiotensinogen levels decreased significantly, and the administration of LPS did not elevate plasma angiotensinogen levels. In contrast, plasma kininogen levels were increased by adrenalectomy, as well as by sham-operation. Dexamethasone significantly increased plasma angiotensinogen levels in adrenalectomized rats as well as in normal rats, but aldosterone did not. Plasma kininogen levels of normal rats were not changed by the administration of dexamethasone or aldosterone. From these results, it was concluded that the acute phase response of plasma angiotensinogen is mediated by glucocorticoid, but that of plasma kininogen is not.

Topics: Acute-Phase Reaction; Adrenalectomy; Aldosterone; Angiotensinogen; Animals; Dexamethasone; Inflammation; Kinetics; Kininogens; Lipopolysaccharides; Male; Rats; Rats, Inbred Strains

Accumulating information concerning the structure of angiotensinogen suggests a resemblance of this component of the renin-angiotensin system to the acute-phase protein alpha 1-antitrypsin. Compared to a group of age- and sex-matched controls without signs of infection, markedly elevated levels of angiotensinogen (increase in median value: 70%), alpha 1-antitrypsin (102%), caeruloplasmin (76%), haptoglobin (261%), and orosomucoid (162%) were found in plasma from 14 patients with acute inflammatory disease. This finding indicates that angiotensinogen should be included in the list of acute-phase proteins in man, and raises the question whether angiotensinogen is involved in the regulation of the renin-angiotensin system during inflammation and tissue injury.

Topics: Acute Disease; Adolescent; Adult; Aged; alpha 1-Antitrypsin; Angiotensinogen; Female; Humans; Inflammation; Male; Middle Aged

Inflammatory responses of the angiotensinogen mRNA in rat liver and brain were examined by RNA blot-hybridization analysis with use of a cDNA probe specific for rat angiotensinogen. The angiotensinogen mRNA in the liver increased rapidly during the first 5 h following the administration of Escherichia coli lipopolysaccharide, and at maximum level of induction, the mRNA increased approximately 5-fold over its normal level. The levels of the mRNA increased with increasing doses of lipopolysaccharide, the half-maximal dose being approximately 1 microgram/100 g body weight. In contrast, no such increase was observed in the brain angiotensinogen mRNA. Thus, the expression of the rat angiotensinogen mRNA is regulated in a tissue-specific manner in response to induction of acute inflammation.

Topics: Angiotensinogen; Angiotensins; Animals; Brain Chemistry; Escherichia coli; Inflammation; Lipopolysaccharides; Liver; Nucleic Acid Hybridization; Rats; Rats, Inbred Strains; RNA, Messenger