angiotensinogen and Hyperaldosteronism

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

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

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

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

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

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

Refractory hyperaldosteronism is frequently observed in heart failure patients on up-to-date treatment, and holds prognostic value. Our aim was to identify which factors, either genetic or nongenetic, are associated with refractory hyperaldosteronism.. We enrolled 109 consecutive patients with left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) 32 ± 10%; 86% males; age 65 ± 13 years (mean ± standard deviation)] on optimized adrenergic and renin-angiotensin-aldosterone system (RAAS) antagonism, undergoing clinical and neuroendocrine characterization, and genotyping for six polymorphisms in key RAAS-regulating genes [angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE-240A>T and I/D), angiotensin II type I receptor (AGTR1 1166A>C), aldosterone synthase (CYP11B2-344C>T) and renin (REN rs7539596)].. Patients with refractory hyperaldosteronism (n = 41, 38%, with plasma concentration >180 ng/l, URL, median 283 ng/l, interquartile range 218-433), when compared with those without (106 ng/l, 74-144; P < 0.001), were not different either for treatment or LVEF, while presented with different AGT M235T genotype distribution (P = 0.047). After adjustment for several humoral, instrumental, functional and therapeutical variables, only plasma renin activity (PRA) (P < 0.001) and potassium (P = 0.027) were independently associated with refractory hyperaldosteronism. Among polymorphisms, only AGT M235T (P = 0.038) was associated with refractory hyperaldosteronism, after adjustment for nongenetic variables.. In conclusion, refractory hyperaldosteronism in heart failure may be influenced by AGT M235T polymorphism, among RAAS candidate genes, and by PRA, which may represent, respectively, a constitutive (genotype dependent) and a nongenetic (phenotype-dependent) trigger for aldosterone elevation.

Topics: Aged; Angiotensinogen; Biomarkers; Cardiovascular Agents; Female; Follow-Up Studies; Gene Frequency; Genetic Predisposition to Disease; Heart Failure; Humans; Hyperaldosteronism; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Prospective Studies; Renin; Renin-Angiotensin System

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

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

Topics: Angiotensinogen; Cardiovascular Diseases; Endocrinology; Endothelins; Ghrelin; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Peptide Hormones; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors

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

Topics: Addison Disease; Angiotensinogen; Biological Assay; Cushing Syndrome; Female; Humans; Hyperaldosteronism; Liver; Male; Pregnancy; Radioimmunoassay; Reference Values; Renin-Angiotensin System

Studies of plasma samples of 3 subjects with Bartter's syndrome were compared to 8 subjects with other conditions. Despite high levels of active renin initially, with low levels of inactive renin, addition of either human nephrectomized plasma or sheep substrate not only increased active renin (by at least 3-fold) but also led to the appearance of large quantities of inactive renin (10-20 times the concentration originally present, much greater than the small increase seen with other plasmas). The activated inactive renin after substrate addition possibly had a larger and more variable molecular size (42,000-48,000) than normal inactive renin (42,500-44,500). Renin substrate in Bartter's plasma was present in similar amounts and had a normal or supranormal angiotensin generation rate with exogenous human renin. Bartter's substrate had a similar molecular weight (55,000) to that found in normal human plasma. The agent in the exogenous substrate preparations causing the increase in apparent active and inactive renin was not ultrafiltrable. However, an acidification procedure that destroyed exogenous substrate also removed the renin-increasing effect. Captopril increased renin but not aldosterone, while amiloride increased aldosterone but not renin. Neither agent improved serum potassium significantly in these patients on indomethacin.

Topics: Adolescent; Aldosterone; Amiloride; Angiotensin I; Angiotensinogen; Animals; Bartter Syndrome; Captopril; Child; Child, Preschool; Enzyme Precursors; Female; Humans; Hydrogen-Ion Concentration; Hyperaldosteronism; In Vitro Techniques; Male; Renin; Sheep

Topics: Adult; Aged; Angiotensinogen; Captopril; Cushing Syndrome; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Liver Cirrhosis; Male; Middle Aged; Sodium Chloride

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

Topics: Aldosterone; Angiotensin II; Angiotensinogen; Corticosterone; Hepatic Encephalopathy; Hepatitis; Humans; Hydrocortisone; Hyperaldosteronism; Liver Cirrhosis; Liver Diseases; Renin