Angiotensinogen Concentration Research Articles

Conjugated Linoleic Acid Supplementation Enhances Antihypertensive Effect of Ramipril in Chinese Patients With Obesity-Related Hypertension

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.

Angiotensinogen gene M235T polymorphism as a predictor of cardiovascular risk in hypertensive adolescents

Purpose : The renin-angiotensin system (RAS) has been demonstrated to play a major role in regulating blood pressure. Therefore, components of the RAS are likely candidate genes that may predispose an individual to essential hypertension and cardiovascular complications. Among them, the M235T polymorphism of the angiotensinogen gene has been speculated to be associated with elevated circulating angiotensinogen concentrations and essential hypertension. This study aimed to analyze the angiotensinogen M235T polymorphism in hypertensive adolescents and investigate its relationship with cardiovascular risks. Methods : Forty Korean hypertensive adolescents (aged 16-17, systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) and fifty seven normal adolescents were included. Obesity index (OI), body mass index (BMI) were calculated. BP was measured by oscillometric methods in resting state. Polymerase chain reaction (PCR) technique was performed on DNA from the hypertensives subjects to analyze the M235T polymorphism. Serum homocysteine, insulin, renin, aldosterone and angiotensin converting enzyme (ACE) were tested according to each genotype. The carotid intima-media thickness (IMT) and carotid artery diameter, Pulse wave velocity (PWV) and ankle-brachial index (ABI) were measured according to each genotype. Results : Genotype frequencies of T/T, M/T and M/M were 62.5%, 35.0%, 2.5%, respectively in hypertensive adolescents. The results were not significantly different compared to control group. Serum insulin, renin levels, BMI and OI were significantly higher in thoses with the M/M genotype as compared to those with the T/T of M/T genotype. Conclusion : This study showed that the M235T polymorphism was not associated with essential hypertension or any cardiovascular risks. Further clinical research is required to ascertain the relationship between this polymorphism and cardiovascular complications in Korean hypertensive adolescents.

Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations

The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS.

Components of the renin‐angiotensin‐aldosterone system in plasma and ascites in hepatic cirrhosis

Decompensated liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid. In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites. Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = -0.73, P < 0.001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0.001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 +/- 11%) was slightly lower than the albumin level (23 +/- 8%), whereas the aldosterone level (43 +/- 18%) was considerably higher (P < 0.0001). For renin and prorenin these percentages were much lower (P < 0.0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in-vitro degradation rates of renin in plasma and ascitic fluid were identical. In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites-to-plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.

Relation Between Renin-Angiotensin-Aldosterone System and Otosclerosis

Angiotensin II (Ang II) may be implicated in the regulation of bone remodeling, and its activity is related to several gene polymorphisms including AGT M235T for plasmatic and tissular concentrations of angiotensinogen (AGT), ACE I/D for the angiotensin-converting enzyme activity, and AT(1)R A/C(1166) for the Ang II receptor function. The objective of this study was to investigate the implication of this hormone in otosclerosis. Prospective case-control study. The above-mentionedpolymorphisms were investigated in 186 patients with otosclerosis and 526 healthy controls, both groups originated from the French Caucasian population. Primary cell cultures of stapedial bone from patients with otosclerosis (n = 6) and control subjects (n = 5) were investigated for the messenger ribonucleic acid expressions of Ang II receptors (Types 1 and 2) and cellular AGT and the effect of Ang II (10(-7) mol/L, 24 h) on the alkaline phosphatase activity and the interleukin-6 secretion in the culture media. A significant association was found between otosclerosis and the AGT M235T and the ACE I/D polymorphisms. Higher proportions of TT (29% versus 16%; p < 0.01) and DD (50% versus 38%; p < 0.05) genotypes were observed in cases versus controls. No association was found between the AT(1)R A/C(1166) polymorphism and otosclerosis. Ang II receptor Types 1 and 2 and AGT were detected in the cultures. Ang II increased the in vitro secretion of interleukin-6 and decreased the alkaline phosphatase activity only in otosclerotic cells. These observations suggest a relation between the local renin angiotensin system activity and otosclerosis, opening new therapeutic insights.

Determination of plasma and urinary angiotensinogen levels in rodents by newly developed ELISA

We recently reported that urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status in angiotensin II-dependent hypertensive rats. Angiotensinogen concentrations in mouse plasma are thought to be much lower than those in rat plasma; however, detailed information is deficient due to lack of direct quantitative measurements of rodent angiotensinogen. To elucidate this issue, we have developed a quantitative method for measurement of rodent angiotensinogen using a sandwich-type ELISA. The standard curve for mouse and rat angiotensinogen exhibited a high linearity at 0.16-10 and 0.08-5 ng/ml, respectively, with correlation coefficients >0.99. While plasma angiotensinogen concentrations of male high serum IgA (HIGA) mice (IgA nephritis model animals, 1,308 +/- 47 ng/ml; n = 10) were lower than those of control BALB/c mice (1,620 +/- 384; n = 12), urinary angiotensinogen concentrations of HIGA mice (14.6 +/- 1.5 ng/ml; n = 34) were higher than those of BALB/c mice (4.6 +/- 0.1; n = 2). In a similar manner, while plasma angiotensinogen concentrations of Zucker diabetic fatty (ZDF) obese rats (type 2 diabetic model animals, 1,789 +/- 50 ng/ml; n = 5) were lower than those of control ZDF lean rats (2,296 +/- 47; n = 5), urinary angiotensinogen concentrations of ZDF obese rats (88.2 +/- 11.4 ng/ml; n = 15) were higher than those of ZDF lean rats (31.3 +/- 1.9; n = 15). These data indicate that plasma and urinary angiotensinogen concentrations are less in mice than rats. However, these data suggest that urinary angiotensinogen levels are different from plasma angiotensinogen levels in rodents. The development of rodent angiotensinogen ELISA allows quantitative comparisons in mouse and rat angiotensinogen levels in models of hypertension and cardiovascular and kidney diseases.

Genetic Variation and Activity of the Renin-Angiotensin System and Severe Hypoglycemia in Type 1 Diabetes

Background The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. Methods Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. Results Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. Conclusions High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

Novel sandwich ELISA for human angiotensinogen

We recently reported that urinary excretion rates of angiotensinogen (U(AGT)) provide a specific index of intrarenal renin-angiotensin (ANG) system (RAS) status in ANG II-dependent hypertensive rats. When this is shown to be applicable to human subjects, a diagnostic test to identify those hypertensive patients most likely to respond to an RAS blockade could provide useful information to allow a mechanistic rationale for selection of an optimized approach to treatment of hypertensive patients. However, simple and accurate methods to measure human angiotensinogen (hAGT) are unavailable. For future studies of human subjects, we developed antibodies and a sensitive and specific quantification system for hAGT using a sandwich ELISA. We raised two antibodies against hAGT: a mouse monoclonal antibody and a rabbit polyclonal antibody. The standard curve of this ELISA exhibited a high linearity (0.31-20 ng/ml). The correlation coefficient was >0.99. Plasma angiotensinogen concentrations of healthy volunteers ranged from 28 to 71 microg/ml (n = 10). The ratio of U(AGT) to urinary creatinine concentration ranged from 5.0 to 30 microg/g (n = 7). Intra- and interassay coefficients of variation ranged from 4.4 to 5.5% and from 4.3 to 7.0%, respectively. This ELISA system had no cross-reactivity with major proteins in proteinuric urine samples, such as human albumin, immunoglobulin, or transferrin. Moreover, the cross-reactivity of the system with angiotensin peptides was also negligible. This hAGT ELISA will be a useful tool to investigate the relationship of U(AGT) and reactivity to antihypertensive drugs in hypertensive patients.

Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen

Objective We evaluated the effects of a new combined hormonal contraceptive vaginal ring (CVR) delivering the nonandrogenic progestin Nestorone® (NES) and ethinyl estradiol (EE) on several key estrogen-sensitive hepatic proteins that may be markers for the risk of arterial or venous disease events and on blood pressure (BP). Because the pharmacologic androgenicity of the progestin in these formulations influences the hepatic impact of EE, we selected an oral contraceptive (OC) delivering the androgenic progestin levonorgestrel (LNG) and EE as the comparator. We also investigated the effect of delivery route, which is known to modify the hepatic effects of estradiol, but has not been widely studied with EE. Study Methods Women, aged 18–34 years, with no contraindications to the use of combined OCs, were randomized to three cycles of treatment with a CVR delivering NES/EE (150/15 μg/day) or a combined OC providing LNG and EE (150/30 μg per tablet). Each cycle consisted of 21 days of active treatment, followed by 7 days without treatment. During the last weeks of the pretreatment and third treatment cycles, blood samples were obtained for determinations of plasma concentrations of angiotensinogen, an estrogen-sensitive hepatic protein, and serum concentrations of sex hormone-binding globulin (SHBG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and estrogen- and androgen-sensitive proteins. BP was also measured. Results Of 47 women randomized, 45 completed the study (CVR: 23; OC: 22). Within-group comparisons over time by repeated-measure analysis of variance demonstrated statistically significant changes over time with both treatments for all hepatic proteins (p<.02) but not for TC. The within-group effects, presented as relative percent difference [95% confidence interval (CI)], were greatest for angiotensinogen [CVR: 227% (195–262%); OC: 251.3% (218–288%)] and SHBG [CVR: 306% (237–389%); OC: 55% (30–86)]. Both treatments were associated with small changes in systolic BP and diastolic BP (DBP), but only the within-group change in DBP for the OC group was statistically significant (p=.04). Between-treatment comparisons of third treatment cycle mean values were performed by analysis of covariance (baseline values as covariate). No statistically significant between-treatment differences were found for angiotensinogen, sensitive only to estrogen, or BP. Statistically significant treatment differences were found for all estrogen- and androgen-sensitive proteins (p≤.002) but not for TC. When presented as relative percent difference between the effects of treatment (CVR-OC/OC; 95% CI of percent difference), the difference was largest for SHBG (159% [117–210%]); smaller relative percent differences were found for HDL-C [31.9% (18.5–46.8%)], LDL-C [23.6% (33.4% to −2.4%)] and TG [39.0% (14.0–69.4%)], but not TC. Conclusion Vaginal delivery of a combined hormonal contraceptive did not reduce the EE-associated changes in estrogen-sensitive hepatic proteins observed after use of a combined OC. Significant treatment differences between the NES/EE CVR and the LNG/EE OC were found for SHBG, HDL-C, LDL-C, and TG, proteins sensitive to androgen as well as estrogen. No treatment difference was observed for angiotensinogen, which is sensitive only to estrogen. The observed treatment differences were therefore most likely due to the difference in androgenicity between NES and LNG.

Endocrine Role of the Renin-Angiotensin System in Human Adipose Tissue and Muscle

The renin-angiotensin system has been implicated in obesity-related hypertension and insulin resistance. We examined whether locally produced components of the renin-angiotensin system in adipose tissue and skeletal muscle play an endocrine role in vivo in humans. Furthermore, the effects of beta-adrenergic stimulation on plasma concentrations and tissue release of renin-angiotensin system components were investigated. Systemic renin-angiotensin system components and arteriovenous differences of angiotensin II (Ang II) and angiotensinogen (AGT) across abdominal subcutaneous adipose tissue and skeletal muscle were assessed in combination with measurements of tissue blood flow before and during systemic beta-adrenergic stimulation in 13 lean and 10 obese subjects. Basal plasma Ang II and AGT concentrations were not significantly different between lean and obese subjects. Ang II concentrations were increased in obese compared with lean subjects during beta-adrenergic stimulation (12.6+/-1.5 versus 8.1+/-1.0 pmol/L; P=0.04), whereas AGT concentrations remained unchanged. Plasma renin activity increased to a similar extent in lean and obese subjects during beta-adrenergic stimulation (both P<0.01). No net Ang II release across adipose tissue and skeletal muscle could be detected in both groups of subjects. However, AGT was released from adipose tissue and muscle during beta-adrenergic stimulation in obese subjects (both P<0.05). In conclusion, locally produced Ang II in adipose tissue and skeletal muscle exerts no endocrine role in lean and obese subjects. In contrast, AGT is released from adipose tissue and muscle in obese subjects during beta-adrenergic stimulation, which may contribute to the increased plasma Ang II concentrations during beta-adrenergic stimulation in obese subjects.

Angiotensin II increases adipose angiotensinogen expression

In addition to the well-defined contribution of the liver, adipose tissue has been recognized as an important source of angiotensinogen (AGT). The purpose of this study was to define the angiotensin II (ANG II) receptors involved in regulation of adipose AGT and the relationship of this control to systemic AGT and/or angiotensin peptide concentrations. In LDL receptor-deficient (LDLR(-/-)) male mice, adipose mRNA abundance of AGT was 68% of that in liver, and adipose mRNA abundance of the angiotensin type 1a (AT(1a)) receptor (AT(1a)R) was 38% of that in liver, whereas mRNA abundance of the angiotensin type 2 (AT(2)) receptor (AT(2)R) was 57% greater in adipose tissue than in liver. AGT and angiotensin peptide concentrations were decreased in plasma of AT(1a)R-deficient (AT(1a)R(-/-)) mice and were paralleled by reductions in AGT expression in liver. In contrast, adipose AGT mRNA abundance was unaltered in AT(1a)R(-/-) mice. AT(2)R(-/-) mice exhibited elevated plasma angiotensin peptide concentrations and marked elevations in adipose AGT and AT(1a)R mRNA abundance. Increases in adipose AGT mRNA abundance in AT(2)R(-/-) mice were abolished by losartan. In contrast, liver AGT and AT(1a)R mRNA abundance were unaltered in AT(2)R(-/-) mice. Infusion of ANG II for 28 days into LDLR(-/-) mice markedly increased adipose AGT and AT(1a)R mRNA but did not alter liver AGT and AT(1a)R mRNA. These results demonstrate that differential mRNA abundance of AT(1a)/AT(2) receptors in adipose tissue vs. liver contributes to tissue-specific ANG II-mediated regulation of AGT. Chronic infusion of ANG II robustly stimulated AT(1a)R and AGT mRNA abundance in adipose tissue, suggesting that adipose tissue serves as a primary contributor to the activated systemic renin-angiotensin system.

Letter by Krop et al Regarding Article, “Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium”

HomeCirculationVol. 114, No. 17Letter by Krop et al Regarding Article, “Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Krop et al Regarding Article, “Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium” Manne Krop, MSc, Joep H.M. van Esch, MSc and A.H. Jan Danser, PhD Manne KropManne Krop Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands Search for more papers by this author , Joep H.M. van EschJoep H.M. van Esch Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands Search for more papers by this author and A.H. Jan DanserA.H. Jan Danser Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands Search for more papers by this author Originally published24 Oct 2006https://doi.org/10.1161/CIRCULATIONAHA.106.642975Circulation. 2006;114:e556To the Editor:Angiotensin (Ang) II generation in the heart depends on blood-derived renin and/or prorenin. Both proteins diffuse into the cardiac interstitium or bind to receptors.1 In the case of prorenin, local prorenin–renin conversion is required to allow angiotensin production at cardiac tissue sites. We therefore read with great interest the article by Itoh et al2 in which the authors claim that the diabetic mouse heart contains upregulated levels of a kallikrein-like prorenin-converting enzyme (PRECE). This is of importance because diabetic subjects are known to have increased prorenin levels.1The authors did not evaluate prorenin activation in the diabetic heart. Instead, they investigated the role of the renin-angiotensin system (RAS) in mice with cardiac-specific overexpression of wild-type p90 ribosomal S6 kinase (WT-p90RSK-Tg). These mice also display increased PRECE levels as compared with nontransgenic littermate control mice (NLC). Recovery of cardiac function after ischemia/reperfusion in WT-p90RSK-Tg isolated hearts was significantly impaired. Both captopril and olmesartan improved cardiac function and reduced infarct size in WT-p90RSK-Tg mice, whereas these RAS blockers exerted no effect in NLC hearts.Densitometric analysis revealed that angiotensinogen in WT-p90RSK-Tg (but not NLC) hearts decreased to undetectable levels within 10 minutes after the start of buffer perfusion. This corresponds with our earlier observation that angiotensinogen washout from buffer-perfused rat hearts occurs with a half-time of <3 minutes.3 A similarly rapid washout was observed for renin,3 and given the identical diffusion rates and receptor-binding kinetics of renin and prorenin,1 cardiac prorenin will likely disappear equally rapidly. Thus, after the 25-minute equilibration period applied by Itoh et al,2 it is unlikely that any (pro)renin or angiotensinogen remains in the isolated perfused heart. The authors claim that the more rapid angiotensinogen disappearance in the WT-p90RSK-Tg heart is suggestive of increased angiotensinogen–Ang I conversion. However, given the kinetics of the renin-angiotensinogen reaction (resulting in pmol/L angiotensin levels at μmol/L angiotensinogen concentrations), near-complete angiotensinogen–Ang I conversion in 10 minutes is very unlikely in our opinion.To explain the beneficial effects of RAS blockers during ischemia/reperfusion in WT-p90RSK-Tg hearts that lack angiotensinogen (as opposed to the lack of effect of these drugs in NLC hearts, in which angiotensinogen washout occurred more slowly), the radical-scavenging properties of sulfhydryl-containing angiotensin-converting enzyme inhibitors (like captopril)4 and the antiarrhythmic (non–Ang II type 1 receptor-mediated) effects of Ang II type 1 receptor antagonists5 should be taken into consideration. Finally, direct angiotensinogen–Ang II conversion by PRECE, as suggested by the authors, seems unlikely, given the undetectable angiotensin levels in hearts of nephrectomized animals in vivo.1The contribution of PRECE to prorenin-renin conversion in the diabetic heart should now be thoroughly investigated. The authors are to be complimented for providing a potential piece of the puzzle that links prorenin to tissue angiotensin generation.DisclosuresDr Danser is the recipient of a Novartis Aliskiren Grant and is a member of the Novartis Aliskiren Advisory Board. The other authors report no conflicts.1 Danser AHJ, Deinum J. Renin, prorenin and the putative (pro)renin receptor. Hypertension. 2005: 46; 1069–1076.LinkGoogle Scholar2 Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, Abe J. Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium. Circulation. 2006; 113: 1787–1798.LinkGoogle Scholar3 de Lannoy LM, Danser AHJ, van Kats JP, Schoemaker RG, Saxena PR, Schalekamp MADH. Renin-angiotensin system components in the interstitial fluid of the isolated perfused rat heart: local production of angiotensin I. Hypertension. 1997; 29: 1240–1251.CrossrefMedlineGoogle Scholar4 Mak IT, Freedman AM, Dickens BF, Weglicki WB. Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol. 1990; 40: 2169–2175.CrossrefMedlineGoogle Scholar5 Thomas GP, Ferrier GR, Howlett SE. Losartan exerts antiarrhythmic activity independent of angiotensin II receptor blockade in simulated ventricular ischemia and reperfusion. J Pharmacol Exp Ther. 1996; 278: 1090–1097.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 24, 2006Vol 114, Issue 17 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.106.642975PMID: 17060392 Originally publishedOctober 24, 2006 PDF download Advertisement SubjectsCardiorenal SyndromeDiabetes, Type 1

Polymorphism in the Angiotensinogen Gene, Hypertension, and Ethnic Differences in the Risk of Recurrent Coronary Events

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.

Angiotensinogen gene polymorphism (Met235Thr) influences visceral obesity and insulin resistance in obese Japanese women

To investigate the relationship between angiotensinogen (AGT) Met235Thr polymorphism (M235T) and human obesity, because AGT is regarded as one of the cytokines produced from adipocytes and serum AGT concentrations are reported to be positively correlated with body mass index. One hundred and twenty obese Japanese women (age, 58.8 ± 9.4 years; body mass index, 32.2 ± 4.9 kg/m 2) were enrolled. Angiotensinogen genotypes were determined with a fluorescent allele-specific DNA primer assay system. Subjects were divided into M/M, M/T, and T/T groups. Control subjects comprised 146 healthy age-matched women. Clinical characteristics and the effects of diet and exercise therapy for 6 months were compared among the 3 genotypes. The genotype frequencies of AGT M235T polymorphism were in accordance with the Hardy-Weinberg equation (obese: M/M, 6.7%; M/T, 27.5%; T/T, 65.8%; control: M/M, 6.8%; M/T, 21.2%; T/T, 71.9%). The frequency of the T allele did not differ between obese and control subjects (0.80 vs 0.83). As the number of obese women with M/M genotype was only 8, comparisons of the characteristics and outcomes of weight reduction therapy were performed only between subjects with M/T genotype and T/T genotype. In the T/T group, % body fat and waist circumference at baseline were significantly greater than in the M/T group (36.3% ± 4.8% vs 33.8% ± 4.7%, P = .0105; 107.9 ± 10.9 vs 102.6 ± 7.9 cm, P = .0428, respectively). Before the weight reduction therapy, significantly higher insulin and higher homeostasis model assessment (HOMA-R) were demonstrated in the T/T group than in the M/T group (9.1 ± 5.5 μU/mL vs 5.9 ± 4.4 μU/mL, P = .0056; 2.3 ± 1.4 vs 1.6 ± 1.3, P = .0252, respectively). Both systolic and diastolic blood pressure at baseline in the T/T group tended to be higher than those in the M/T group, but the differences were not significant. No genotype-dependent difference in energy expenditure or outcome of weight reduction therapy was observed with respect to AGT M235T polymorphism. After the diet and exercise therapy, the blood pressure in the T/T group tended to be higher than that in the M/T group, but the difference was not significant. We demonstrated that the T/T genotype of the AGT M235T gene polymorphism was positively related to visceral obesity and hyperinsulinemia in obese Japanese women. Blood pressure did not show genotype-specific differences before or after the treatment. Further studies of the association between obesity and this gene polymorphism should contribute to understanding and treating obesity-related diseases.

Angiotensin II increases blood pressure and functional expression of alpha1D‐adrenoceptors in aorta of adult Wistar rat

Angiotensin II (Ang II) plays an important role in regulating systemic arterial pressure. Interestingly, it is known that RAS components are enhanced in young SHR (plasma renin activity and angiotensinogen concentration); these components might contribute to pathogenesis of genetic hypertension. In the cardiovascular system α1-adrenoceptors regulate processes like cardiac and arterial smooth muscle contraction and they have been implicated in pathological processes such as cardiac hypertrophy or ischemia-induced cardiac arrythmias. The aim of this work was to explore the in vivo Ang II continuous effect on α1D−adrenoceptors functional expression in aorta of Wistar rats. Osmotic minipumps (Alzet) filled with Ang II (release of 200 ng/kg/min/14 days) were subcutaneously implanted in male Wistar rats of 3 months of age. Arterial blood pressure was measured by a tail-cuff method; after 2 weeks aorta was isolated and used for contractile experiments. Ang II induced an early increase in blood pressure and a maximal effect at 10 days (178 ± 10 vs 110 ± 5 mmHg). Phenylephrine-induced contraction in aorta was greater (4.2 ± 0.3 g maximal effect) in Ang II-treated rats than in controls (2.7 ± 0.4 g). The data suggest that Ang II-induced hypertension might be mediated by α1D− adrenoceptors augmented expression. It will be very interesting to determine the mRNA and protein of α1D− adrenoceptors in aorta of Ang II treated rats. Supported in part by grants 47481 from Conacyt (RV-M) and PAPIIT IN210702 (MI).

Laughter therapy modulates the parameters of renin-angiotensin system in patients with type 2 diabetes

The effect of laughter therapy on the plasma levels of renin, angiotensinogen, and prorenin was investigated in patients with type 2 diabetes. In the diabetic patients, the mean plasma renin concentrations were 24.6+/-12.1 ng/ml/h in the first observation (at the beginning of laughter therapy), 8.2+/-3.4 ng/ml/h in the second observation (three months after the beginning of laughter therapy) and 7.7+/-1.7 ng/ml/h in the third observation (six months after the beginning of laughter therapy). The mean plasma angiotensinogen concentrations in the 1st, 2nd and 3rd observations were 0.19+/-0.08, 0.47+/-0.12, 0.42+/-0.14 microg/ml, respectively. The mean plasma prorenin concentrations in the 1st, 2nd and 3rd observations during the laughter therapy were 195.1+/-66.2, 193.4+/-88.2 and 170.7+/-52.5 pg/ml, respectively. Plasma renin concentrations were significantly decreased (p<0.05) by the therapy. Subnormal concentrations of plasma angiotensinogen were found in the 1st observation and increased significantly (p<0.05) to the normal range after the therapy. Plasma prorenin concentration only slightly changed during the laughter therapy. Other biochemical parameters remained unchanged during the laughter therapy. These results indicated that a long-term laughter therapy changed the plasma components of renin-angiotensin system in patients with diabetes. Thus, laughter therapy can be used as non-pharmacological treatment for the prevention of diabetic microvascular complications.

Effects of a reduction in maternal renal mass on pregnancy and cardiovascular and renal function of the pregnant ewe

Maternal renal disease is associated with high maternal and fetal morbidity. To establish an animal model to study renal dysfunction in pregnancy and its potential role in programming for renal disease and hypertension in adult life, a kidney was removed from each of 16 nonpregnant ewes, and a branch of the renal artery of the remaining kidney was ligated (STNx ewes). The 16 STNx and 15 intact ewes were time mated 2.5-17 mo later and studied at 119-132 days of gestation. STNx ewes demonstrated renal hypertrophy and glomerular hyperfiltration. They had higher diastolic arterial pressures (P < 0.05) and larger left ventricles (P < 0.0005), drank more water (P < 0.01), were hypochloremic (P < 0.01) and hyperglycemic (P < 0.0005), and had higher plasma creatinine levels (P < 0.0005) than intact ewes. Effective renal plasma flows and glomerular filtration rates were lower (P < 0.01) and protein excretion was greater (P < 0.05) in STNx than in intact ewes. Glomerulotubular balance was impaired in STNx ewes. Proximal tubular Na(+) reabsorption was reduced (P < 0.05), so Na(+) excretion was increased (P < 0.05). In STNx ewes, filtered K(+) loads were reduced (P < 0.005), but K(+) excretion was the same as in intact ewes. There was net K(+) secretion in STNx ewes; in intact ewes, there was net reabsorption. Plasma renin and angiotensinogen concentrations in STNx and intact ewes were similar, so the hypertension in STNx ewes was not renin dependent. STNx fetuses grew normally, and their blood gases, blood pressure, and heart rates were normal. These alterations in maternal fluid and electrolyte balance and the potential risk of maternal salt depletion or hyperkalemia may adversely affect the fetus.

Renin, Prorenin and the Putative (Pro)renin Receptor

Renin is an aspartic protease that consists of 2 homologous lobes. The cleft in between contains the active site with 2 catalytic aspartic residues.1 Unlike other aspartic proteases such as pepsin or cathepsin D, renin is monospecific and only cleaves angiotensinogen, to generate angiotensin (Ang) I. Ang I is the precursor of the active end-product of the renin-angiotensin system (RAS), Ang II. Renin has also been called active renin to underline that an enzymatically inactive form of renin exists. In 1971, Lumbers found that amniotic fluid, left at low pH in the cold, acquired renin activity.2 Later, Skinner described a similar phenomenon in plasma.3 Acidification was not strictly necessary for this increase in Ang I-generating activity, because incubation at low temperature also increased renin activity, albeit to only 15% of activity after acidification. Soon it was postulated that this inactive, but activatable “big” renin (its molecular weight was 5 kDa higher than that of renin) was the biosynthetic precursor of renin. Hence, it was named prorenin. Only with the cloning of the renin gene in 1984 was prorenin definitively proved to be the precursor of renin.4 For reasons that are unknown, prorenin circulates in human plasma in excess to renin, sometimes at concentrations that are 100-times higher.5 Prorenin has also been demonstrated in plasma of cat, dog, cattle, pig, horse, sheep, rabbit, rat, and mouse. A 43-amino acid N-terminal propeptide explains the absence of enzymatic activity of prorenin. This propeptide covers the enzymatic cleft and obstructs access of angiotensinogen to the active site of renin. (Pro)renin is synthesized as a preprohormone. It contains a signal peptide that directs the protein to the endoplasmic reticulum and ultimately to the exterior of the cell. Both renin and prorenin can be fractionated into multiple species by isoelectric focusing. …

Hypercholesterolemia Stimulates Angiotensin Peptide Synthesis and Contributes to Atherosclerosis Through the AT 1A Receptor

Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT1 receptors or AT1A receptor deficiency. However, the mechanism underlying the pronounced responses to angiotensin II (Ang II) antagonism has not been determined. We hypothesized that hypercholesterolemia stimulates the production of angiotensin peptides to provide a rationale for the profound effect of AT1A receptor deficiency on atherogenesis. Atherosclerotic lesions were analyzed in LDL receptor-deficient mice. Immunocytochemical analysis demonstrated that atherosclerotic lesions contained all the components of the conventional pathway for Ang II synthesis. AT1A receptor deficiency caused a marked decrease in atherosclerotic lesion size in both the aortic root and arch of male and female mice, without a discernible effect on composition. AT1A receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT2 receptor mRNA expression was not altered in AT1A receptor-deficient mice, and AT2 receptor deficiency had no effect on lesion area or cellular composition. Hypercholesterolemia greatly augmented the systemic renin-angiotensin system, as demonstrated by large increases in plasma concentrations of angiotensinogen and angiotensin peptides (Ang II, III, IV, and 4-8). These increases were ablated in hypercholesterolemic AT1A receptor-deficient mice. AT1A receptor deficiency had a striking effect in reducing hypercholesterolemia-induced atherosclerosis in LDL receptor-negative mice. Hypercholesterolemia was associated with increased systemic angiotensinogen and angiotensin peptides, which were reduced in AT1A receptor-deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT1A receptor deficiency in reducing atherosclerosis.

Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension.

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.