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At least 19 recordsLinked to original sources

PubMed2025

Impact of AGT rs5050(T>G) variants on associations between estradiol and angiotensinogen levels: Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: Angiotensinogen plays an essential role in maintaining circulatory homeostasis. AGT rs5050(T > G) has been identified as a regulator of the transcription of AGT mRNA, with differential expression between sexes. We sought to determine if rs5050(T > G), an estrogen response element, modifies the relationship between estrogen and angiotensinogen levels. METHODS: rs5050(T > G) was genotyped, and plasma angiotensinogen levels were measured in 4,831 MESA participants, including postmenopausal women, on hormone therapy (n = 709) or not (n = 1,551), and 2,581 men. Linear regression models were employed to determine the associations of angiotensinogen with rs5050(T > G) allele dosage; and to evaluate whether rs5050(T > G) modifies the association between estradiol and angiotensinogen, with a main effect term and interaction term between rs5050(T > G)*estradiol. Estimated marginal means (EMMs) were used to further evaluate the effect of estradiol on angiotensinogen across different rs5050 alleles (T > G). RESULTS: rs5050TT had the highest median levels of angiotensinogen, followed by TG and GG. Adjusted main effect model showed positive associations between estradiol and angiotensinogen, with each rs5050T allele associated with 0.329 SD higher log-angiotensinogen levels (CI 95% 0.293, 0.365). The interaction rs5050(T > G)*estradiol was not significant, with EMMs exhibiting overlapping slope confidence intervals across genotypes. The proportion of the variance in angiotensinogen explained by modeling increases from 47.9% to 51.6% when including rs5050(T > G) or interation rs5050(T > G)*estradiol in the model. CONCLUSIONS: rs5050(T > G) is associated with circulating angiotensinogen levels, but rs5050(T > G) alleles do not influence the relationship between estradiol and angiotensinogen. This suggests that estrogen's effect on angiotensinogen regulation occurs independently of rs5050(T > G), despite its location within an estrogen-responsive element.

Angiotensinogen↗

PubMed1977

Human angiotensinogen. Purification partial characterization, and a comparison with animal prohormones.

The renin-angiotensin system appears to play a major role in the regulation of sodium excretion and fluid intake in a wide variety of animal species from mammals to teleosts. In mammals the system has evolved further importance in terms of blood pressure homeostasis. This hormonal system in all species appears to involve a serum protein prohormone, angiotensinogen, a proteolytic enzyme, renin, and angiotensin I, the decapeptide product of the reaction between renin and angiotensinogen. The importance of this system to the organism appears to correlate directly with the necessity to conserve sodium while an abnormality of this process may underlie the development of hypertension in man. As the starting point of the system, angiotensinogen assumes special importance as a possible index of evolutionary development. In addition, it has been known for many years that human (viz. primate) angiotensinogen differs from that found in other mammals in its inability to be a substrate for animal renins while animal angiotensinogens readily react with human renin. Thus, the enzymatic specificity appears to reside with the prohormone. The biochemical basis for this difference is unresolved due primarily to the lack of purified human angiotensinogen. In this paper we describe methods for the purification of human angiotensinogen which have direct applicability to animal angiotensinogens. Our approach utilizes ammonium sulfate precipitation, Sephadex G-150 chromatography, multiple isoelectric focusing, and concanavalin A-Sepharose affinity chromatography. With the availability of highly purified human angiotensinogen we compared the molecular weights, heterogeneity, isoelectric points, and thermal lability of hog, rabbit, and human angiotensinogen in order to define the biochemical basis of the species variation in renin reactivity...

Angiotensin II↗

PubMed2025

Genome-wide association study of angiotensinogen levels and key single nucleotide polymorphism associations with blood pressure.

OBJECTIVE: The renin angiotensin aldosterone system plays a key role in circulatory homeostasis. We sought to identify genetic determinants of measured plasma angiotensinogen levels and subsequently evaluate the association of these single nucleotide polymorphisms (SNPs) with blood pressure (BP) and hypertension in a multiethnic population. METHODS: Genome-wide association study (GWAS) of plasma angiotensinogen levels, measured using an enzyme-linked immunoassay, was conducted in 4899 Multi-Ethnic Study of Atherosclerosis (MESA) participants (self-identified as White, n = 1865; Hispanic, n  = 1113; Black, n  = 1224; and Chinese, n  = 629). Linear and logistic models examined the association between SNPs with angiotensinogen and hypertension, respectively. Mediation analysis evaluated the effect of angiotensinogen on BP/hypertension through the top SNPs identified by GWAS. RESULTS: In the analysis utilizing all participants, 115 SNPs were associated with angiotensinogen ( P  < 5 × 10 -8 ), including lead SNP rs4762(G>A) in exon 2 ( P  = 1.51E -100 ) and rs5050(T>G) in the promoter region ( P  = 2.26E -69 ) of the AGT gene. Race/ethnic-specific analyses identified rs4762(G>A) as the lead SNP for White and Hispanic participants, whereas Black and Chinese participants had rs5050(T>G) and rs16852311(G>C), respectively. Both rs4762(G>A) and rs5050(T>G) indirectly increased systolic BP, diastolic BP, and the odds of hypertension through its effect of increasing angiotensinogen. CONCLUSIONS: Our findings demonstrate racial/ethnic differences in genetic effects on angiotensinogen levels across multiple SNPs. AGT rs4762(G>A) and rs5050(T>G) impact BP and hypertension through a mediated effect via angiotensinogen, though opposing direct effects may mask the overall association.

Humans↗

PubMed1978

Regional distribution of angiotensinogen in rat brain.

The regional distribution of angiotensinogen, the prohormone of angiotensin I, was examined in rat brain. Quantification of brain angiotensinogen concentration was difficult because of the presence of an endogenous angiotensin I degrading (i.e. angiotensinase) activity which was active at the pH of the renin-angiotensinogen incubation. This degrading activity was unequally distributed throughout the brain, and its presence in homogenates invalidated measured levels of angiotensinogen. Only following removal of the angiotensinase activity by ammonium sulfate precipitation of the prohormone could the distribution of the prohormone be determined. Angiotensinogen was widely distributed throughout 31 brain regions; however there was an approximate 12-fold variation in concentration. Highest levels of the prohormone were found in the dorsal and ventral periventricular hypothalamus, area postrema, organum vasculosum lamina terminalis, periventricular thalamus, dorsal raphe and lateral reticular formation. Significantly lower amounts were found in the parietal cortex, cerebellum, septum and pituitaries. While the majority of regions examined exhibited similar concentrations of angiotensinogen, the demonstration of regions containing either significnatly low or high amounts of prohormone is consistent with a topographical distribution of angiotensinogen in rat brain.

Amygdala↗

PubMed1979

Partial purification of dog angiotensinogen.

Dog angiotensinogen was purified 450-fold from the plasma of nephrectomized dogs by a simple four-step procedure involving precipitation between 1.5 and 2.3 M ammonium sulfate, gel filtration on Sephadex G-150, ion-exchange chromatography on DE-52 cellulose, and affinity chromatography on Concanavalin A-Sepharose. The purity of the final preparation was over 50%. The preparation of dog angiotensinogen had an apparent molecular weight of 80,000 determined by gel filtration on Sephadex G-100. Kinetic studies indicated that the Km of the reaction of dog renin with partially purified dog angiotensinogen (1,840 pmol/ml) was similar to that for the reaction with angiotensinogen in diluted dog plasma (1,820 pmol/ml). Thus the purification procedures employed did not alter the affinity of dog renin for the Leu10-Leu11 bond of dog angiotensinogen. Because the concentration of angiotensinogen in dog plasma is about 700 pmol/ml, a first order reaction with respect to substrate is indicated in vivo.

Angiotensinogen↗

PubMed1979

Localization of angiotensinogen in rat liver by immunocytochemistry.

Plasm angiotensinogen, the protein precursor of angiotensin, is produced by the liver. The present study investigated the location of angiotensinogen in sections of rat liver using the unlabeled peroxidase-antiperoxidase bridge technique of Sternberger. Specific reaction products of the antibody localization method were most pronounced in the cytoplasm of hepatocytes in the pericentral zone of the liver lobule. Controls, in which antibody was preabsorbed with angiotensinogen, did not form reaction product. The gradient of angiotensinogen observed within liver lobules resembled that demonstrated by metabolic zonation. The distribution of angiotensinogen differed from the scattered distributions found for other plasma proteins.

Angiotensinogen↗

PubMed1978

Characterization of human angiotensinogen.

In this study of the physical and chemical properties of human angiotensinogen were determined. Human angiotensinogen is a glycoprotein containing 14% carbohydrate. The molecular weight as determined by sedimentation equilibrium studies was 56,800. A higher molecular weight was obtained on sodium dodecyl sulfate electrophoresis. Ferguson-type plots indicated that angiotensinogen is another glycoprotein which behaves anomalously on sodium dodecyl sulfate electrophoresis. The COOH-terminal amino acid was found to be serine while two NH2-terminal amino acids, alanine and aspartic acid (or asparagine), were detected. The specific angiotensin I content of angiotensinogen preparations can vary considerably with no effect on the apparent homogeneity of the isolated protein. A protein with negligible angiotensin I content has been obtained from a preparation of human angiotensinogen. The COOH-terminal amino acid of this protein was serine while the only NH2-terminal amino acid detected was alanine.

Amino Acids↗

PubMed1975

Use of an angiotensin II antagonist (saralasin) in the recognition of "angiotensinogenic" hypertension;.

The possibility has been explored of using a specific angiotensin ii antagonist, saralasin (P-113, 1-sar-8-ala-angiotensin ii) to recognize patients whose hypertension depends upon excessive angiotensin ii activity. Among 60 hypertensive patients, saralasin infusion reduced blood pressure in 16 "responders," but not in 44 "nonresponders." The "responders" had the following findings: elevated plasma renin activity in renal vein (or veins) or peripheral veins or both (16 of 16); reduced renal blood flow, shown by arteriography, isotopic studies or pyelography (15 or 16), or progressive azotemia (one of 16); and reduction in blood. These findings indicated that angiotensin ii probably caused hypertension in the "responders," One "nonresponder" had renal vein levels of plasma renin activity suggestive of angiotensinogenic hypertension. Since hypertension was invariably angiotensinogenic when it was reduced by saralasin and, with one possible exception, was never angiotensinogenic in "nonresponders," the antagonist appears to provide an efpressure to or toward normal after corrective operation (four of four) or propranolol therapy (eight of eight). fective means of recognizing angiotensinogenic hypertension.

Adult↗

PubMed1979

Purification and characterization of rat angiotensinogen.

1. Angiotensinogen (renin substrate) was purified from plasma of nephrectomized rats by a four step procedure using ammonium sulfate fractionation, chromatography on Blue Sepharose CL-6B and SP-Sephadex C-50, and gel filtration on Sephadex G-150. 2. The final preparation had a specific concentration of 9.3 microgram angiotensin I/mg (mean of six separate runs). The best preparation so far obtained contains 14.6 microgram angiotensin I/mg protein, which represents a purity of 62%. 3. By sodium dodecyl sulfate disc electrophoresis an apparent molecular weight of 56,400, and by isoelectric focusing an isoelectric point of 4.85 has been determined. These properties of rat angiotensinogen are similar to those reported for human angiotensinogen.

Angiotensinogen↗

PubMed1979

Human plasma angiotensinogen: a review of purification procedures.

The current status of the purification and characterization of human angiotensinogen is reviewed. One problem encountered in the past has been the copurification of a protein with similar porperties. This protein has tentatively been designated alanine-protein. An efficient separation of angiotensinogen and alanine-protein was obtained on a zinc chelate column. Alanine-protein has been purified and its amino acid and carbohydrate composition determined. The COOH-terminal amino acid and the NH2-terminal amino acid were determined to be serine and alanine, respectively. Alanine-protein exhibited multiple forms on isoelectric focusing.

Amino Acids↗

PubMed1976

[Diurnal profiles of plasma aldosterone, cortisol, renin, angiotensinogen and angiotensinases in normal subjects (author's transl)].

Plasma cortisol and renin were estimated in 1 h intervals, plasma aldosterone, angiotensinogen and angiotensinases in 3 h intervals over periods of 24 h in six normal volunteers (age 20-26) under control conditions and subsequently under suppression of ACTH release by dexamethasone. Highest cortisol levels were found around 7 a.m., minimum levels between 9 p.m. and 1 a.m. Dexamethasone reduced cortisol to constantly low concentrations. Aldosterone was highest around 4 a.m. under control conditions and under dexamethasone, and showed lowest concentrations between 4 and 10 p.m. There were no significant differences between mean aldosterone concentrations at corresponding time points of the control and the dexamethasone period. Similar to aldosterone, renen showed peak values around 4 a.m. All mean values at corresponding time points between 7 a.m. and 11 p.m. and the 24 hour mean values of each subject were significantly increased under the influence of dexamethasone. No evidence could be achieved for the existence of circadian rhythms of angiotensinogen and angiotensinases. Dexamethasone did not cause significant changes of these parameters.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Exchangeable sodium in angiotensinogenic and nonangiotensinogenic renovascular hypertension.

Previous studies have suggested that angiotensin II and sodium can act as alternative mechanisms in maintaining high blood pressure in chronic renovascular hypertension, In the present study, exchangeable sodium was measured in rats in which angiotensin II has been confirmed or excluded as the main cause of the hypertension. To determine the degree of participation of angiotensin II in the maintenance of the high blood pressure, we studied the mean blood pressure response to an angiotensin antagonist (1-Sar-8-Ala-angiotensin II) and to a converting enzyme inhibitor (SQ20,881). Rats with a decrease in blood pressure of less than 20 mm Hg, in response to both inhibitors, were classified as nonresponders; those with a decrease of 20 mm Hg or more, as responders. Fifty percent of the rats with two-kidney hypertension were nonresponders, and they had lower blood pressure and plasma renin activity than the responders. Further, these two-kidney, hypertensive, nonresponder rats had normal exchangeable sodium. The two-kidney hypertensive responders, on the other hand, had significantly higher exchangeable sodium than both the two-kidney, hypertensive nonresponders and the two-kidney control rats. These results suggest that angiotensin II and exchangeable sodium do not play a major role in the maintenance of the high blood pressure in the two-kidney hypertensive nonresponders. However, there appears to be an abnormal relationship between renin and exchangeable sodium in the two-kidney hypertensive responders that could contribute to the maintenance of the hypertension.

Angiotensin I↗

PubMedDate not supplied

Evidence against acetone-soluble renin inhibitors in normal human plasma.

The presence of acetone-soluble renin inhibitors in normal plasma has been proposed to explain the variation of plasma reactivity (PRR) in samples from normotensive and hypertensive subjects. In our experience, acetone extraction decreased PRR in relation to unextracted control values, an observation which is not consistent with the circulating lipid-renin inhibitor hypothesis. Exposure to acetone at -40 degrees C for 1 minute invariably denatured some endogenous angiotensinogen. The PRR in extracted and unextracted plasma was positively correlated with the concentration of available angiotensinogen, r = 0.955 (p < 0.05), and r = 0.964 (p < 0.01), respectively, but the addition of exogenous substrate did not uniformly increase PRR in acetone-treated plasma above control values. These data argue against the use of acetone extraction to demonstrate the existence of circulating lipid-renin inhibitors. Acetone removed 14% to 25% of the normal plasma lipids and although the extract contained most of the major lipid classes, neutral lipids were the most abundant (73% by weight). The presence of acetone-soluble phospholipids appeared to increase angiotensin I formation in the partially purified renin-angiotensinogen system, but phospholipids interfered with the radioimmunoassay and resulted in an overestimation of angiotensin I. Plasma neutral lipids decreased in vitro renin activity by 13% (p < 0.025) but this degree of inhibition suggests that lipid-renin interactions may have minimal in vivo physiological significance. In contrast to previous reports, we found the correlation between PRR and endogenous angiotensinogen in normotensive and hypertensive plasmas to be statistically significant (r = 0.643, p < 0.01). Inactivated human angiotensinogen was also shown to be an inhibitor of renin in vitro. This effect could have possibly influenced PRR values that were determined by others in the presence of inactivated angiotensinogen.

Acetone↗

PubMed1978

Purification and partial characterization of rat brain acid proteinase (isorenin).

1. Isorenin was purified 2000-fold from rat brain by a simple 3-step procedure involving affinity chromatography on pepstatinyl-Sepharose, The preparation appears as a homogenous protein in analytical polyacrylamide gel electrophoresis. Sodium dodecyl sulfate gel electrophoresis indicated an apparent molecular weight of 45 000. Isoelectric focusing separated isoenzymes with isoelectric points at pH 5.45, 5.87, 6.16 and 7.05. 2. The enzyme generates antiotensin I from tetradecapeptide (pH optimum 4.7) and from sheep angiotensinogen (pH optima 3.9 and 5.5). The rate of angiotensin I formation from tetradecapeptide was 30 000 times higher than that from sheep angiotensinogen. The enzyme has acid protease activity at pH 3.2 with hemoglobin as the substrate and pepstatin is a potent inhibitor of the enzyme with a Ki of less than 10(-9) M. 3. The properties of the enzyme strongly suggest that it is identical with cathepsin D.

Angiotensin I↗

PubMed1977

Pure Renin. Isolation from hog kidney and characterization.

The pressor enzyme renin (EC 3.4.99.19) was isolated in a pure and stable form from hog kidney by affinity chromatography on a pepstatin/agarose gel followed by three additional steps of conventional chromatography. Destruction of the enzyme by proteolysis during isolation was prevented by chemically eliminating proteases in extracts. The pure preparation was used for the characterization of this enzyme. Renin was found to be a glycoprotein containing glucosamine and possessing binding affinity to concanavalin A. Contrary to previous reports, pure renin is stable at neutral pH either at 4 or -20 degrees for 3 to 8 weeks. It has a molecular weight of 36,400 as determined by equilibrium ultracentrifugation, an isoelectric point of 5.2 and E1%1cm (280 nm) of 9.1. In contrast to crude preparations, the enzyme activity has a broad pH optimum between pH 5.5 and 7.0 for both hog angiotensinogen and the synthetic octapeptide substrate benzyloxycarbonyl-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-beta-naphthylamide. The rate of formation of angiotensin I from hog angiotensinogen at pH 6.0 and 37 degrees was 267 microng/h/microng of renin, or 2000 Goldblatt units/mg of renin. For the synthetic fluorogenic octapeptide substrate benzyloxycarbonyl-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-beta-naphthylamide, a Km of 33 micronM and a Vmax of 0.94 micronmol/h/mg of enzyme were obtained at pH 6.5 and 37 degrees.

Angiotensinogen↗

PubMed1975

Improvement of renin determination in human plasma using a commonly available renin standard in a radioimmunological method.

UNLABELLED: A new method for the measurement of renin in human plasma is described. The method is based on the introduction of the internationally available renin standard of the Medical Research Council (MRC) London, as a calibration system. Thus, some principal disadvantages of methods expressing results in renin reaction velocity (angiotensin generation rate) only are avoided. Both renins, unknown and standard, react with a sheep substrate preparation and are handled identically throughout the whole procedure including the angiotensin I radioimmunoassay (RIA). The plasma renin concentration (PRC) is given in 10(-6) MRC-renin units (muM/ml). RESULTS: the renin standard is free of angiotensin, angiotensinases, and angiotensinogen; it is stable on storage. Identical enzyme kinetics are shown for both renins. An interference between endogenous and exogenous substrate could be avoided. The potentially harmful influences of proteins from the enzyme incubation mixture of the RIA dose response curve are shown. The use of an angiotensin I calibration system could be omitted. Using a standard renin dilution from 250-0.9 muU/ml also the full biological range is covered. When giving an unrestricted diet the preliminary normal values of PRC are 21.9 +/- 12.6 muU/ml in recumbent and 40.1 +/- 19.8 muU/ml in upright position (n = 16,x +/- s, age 20-35 years). Earlier findings of age-dependency of PRC were confirmed.

Adult↗

PubMed1976

Methodologic problems in plasma renin activity measurements.

The influence of pH and angiotensinase inhibitors on the in vitro generation of angiotensin I during PRA measurements has been investigated. PRA values obtained at pH 5.7 are higher than those obtained at pH 7.4. At pH 5.7, values obtained using diisopropylfluorophosphate (DRP 9 mM) as an angiotensinase inhibitor are higher than values obtained with a mixture of dimercaprol (BAL, 1.6 mM) and hydroxyquinoline (8-OHQ, 3 to 4 mM). Since the two methods for inhibiting angiotensinase are completely and equally efficient, it is suggested that these inhibitors might interfere with the renin angiotensinogen reaction. Significant correlations are observed between the PRA values obtained by the different methods which have been studied. Using an incubation pH of 5.7, and BAL and 8-OH quinoline as angiotensinase inhibitors, the distribution of PRA values in a population of 124 hospitalized hypertensive patients ingesting a normal sodium diet had been studied, and it has been demonstrated that the sensitivity of this method of measurement can detect small changes in PRA in patients with low renin activity.

Adenoma↗

PubMed2026

Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs.

We previously reported that excessive angiotensin-II→AT receptor-1 (AT→ATR1) signaling results in sickle cell anemia-associated (SCA-associated) nephropathy. Herein, we showed that hyperangiotensinemia in SCA results from high erythroid cell-generated reactive oxygen species (ROS), which oxidized angiotensinogen (ATGN) and favored its rapid conversion to AT. Increased AT→ATR1 signaling in SCA erythroid cells generated ROS and created a positive feedback loop of ROS→oxidized ATGN→AT→ATR1→ROS, perpetuating the hyperangiotensinemia. ATR1 blocker, losartan, reduced erythrocyte ROS, oxidized ATGN, and AT levels. The ROS→AT→ATR1→ROS loop was driven by sickle erythropoiesis, as it was reproduced when WT mice were transplanted with SCA hematopoiesis. Using SCA and WT mice with germline- and erythroid-specific ATR1 deficiency, we found that stress erythropoiesis, but not steady-state erythropoiesis, was critically dependent on erythroid AT→ATR1 signaling, which acted in harmony with increased erythropoietin signaling. Furthermore, instead of the canonical AT→ATR1→NADPH-oxidase→ROS signaling in steady-state erythropoiesis, AT→ATR1 signaling in stress erythroid cells increased mitochondrial mass and dysfunctional mitochondria, which thereby increased ROS. SCA mice with erythroid-specific ATR1 deficiency had decreased RBC accumulation of dysfunctional mitochondria and decreased ROS, which reduced SCA-associated nephropathy. Overall, we demonstrate that AT→ATR1 signaling was essential for stress erythropoiesis but led to increased dysfunctional mitochondria retention in mature RBCs, which generated ROS and perpetuated hyperangiotensinemia, resulting in end-organ damage.

Animals↗