Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To define the basis of the heterogeneity of angiotensinogen, we have characterized the immunoreactivity of high molecular weight (HMW) and low molecular weight (LMW) plasma angiotensinogen, the angiotensinogen precursor synthesized by cell-free translation, and angiotensinogen secreted by human hepatoma (Hep G2) cells. Angiotensinogen precursor synthesized by rabbit reticulocyte lysate primed with RNA prepared from liver or Hep G2 cells was compared with angiotensinogen secreted by Hep G2 cells by using immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). So as to assess the contribution of N-glycosylation of angiotensinogen, Hep G2 cells were incubated in the presence of tunicamycin. Glycosylation of secreted angiotensinogen was further characterized by using chromatography on concanavalin A-Sepharose, digestion with neuraminidase, and treatment with trifluoromethane sulfonic acid. In Sephadex G-200 column chromatography, HMW plasma angiotensinogen eluted just after the column void volume and was clearly separated from LMW angiotensinogen which eluted just before bovine serum albumin. Both HMW and LMW plasma angiotensinogen were shown to bind to monoclonal and polyclonal antibodies raised against pure LMW angiotensinogen. Only one angiotensinogen precursor (mol wt 50,000) was identified by cell-free translation which, after cleavage by renin, was reduced to mol wt 45,600. Angiotensinogen secreted by Hep G2 cells showed electrophoretic heterogeneity (mol wt 53,100-65,400). Tunicamycin-treated Hep G2 cells secreted five discrete forms of angiotensinogen, a predominant form of mol wt 46,200, with other forms (mol wt 46,800, 48,100, 49,200, and 49,600) representing 10% of secreted angiotensinogen. All five forms showed a similar reduction in molecular weight after cleavage by renin. The predominant 46,200-mol wt protein represented nonglycosylated angiotensinogen in that, after cleavage by renin, it had an electrophoretic mobility (mol wt 45,600) identical to the desangiotensin I-angiotensinogen resulting from renin cleavage of the angiotensinogen precursor. The other higher molecular weight forms of angiotensinogen secreted by tunicamycin-treated Hep G2 cells were shown to represent O-glycosylated angiotensinogen in that they were reduced to 46,200 mol wt by treatment with trifluoromethane sulfonic acid. Dexamethasone (10(-7) and 10(-6)M) stimulated angiotensinogen secretion by Hep G2 cells two- to fourfold, both in the absence and presence of tunicamycin. However, a small stimulatory effect of mestranol (10(-7) M) was evident only in the presence of tunicamycin. Neither dexamethasone nor mestranol influenced the electrophoretic pattern (SDS-PAGE) of angiotensinogen secreted by Hep G2 cells. However, when incubation media were chromatographed on Sephadex G-200 with subsequent immunoprecipitation of the column fractions, both dexamethasone and mestranol were shown to stimulate the secretion of HMW angiotensinogen (eluting just after the column void volume) which, on SDS-PAGE, migrated in a position identical to LMW angiotensinogen. From these studies, we conclude that all forms of human angiotensinogen are derived from a single precursor. The heterogeneity of secreted angiotensinogen represents differences in posttranslational processing of angiotensinogen. This processing includes both N- and O-glycosylation, and also the formation of HMW complexes (HMW angiotensinogen) through association either with other angiotensinogen molecules or with some other protein(s) whose secretion by hepatocytes is stimulated by glucocorticoids and estrogens.
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PMID:Characterization of precursor and secreted forms of human angiotensinogen. 298 36

To define the role of local synthesis of angiotensinogen in tissue angiotensin production, we have quantitated angiotensinogen messenger RNA (mRNA) levels in 17 different tissues of four groups of rats: control rats, nephrectomized rats, rats given dexamethasone, ethynylestradiol, and triiodothyronine, and nephrectomized rats given dexamethasone, ethynylestradiol, and triiodothyronine. Angiotensinogen mRNA was identified in 12 tissues: liver, kidney, brain, spinal cord, aorta, mesentery, atria, lung, adrenal, large intestine, stomach, and spleen. Angiotensinogen mRNA was not identified in pituitary, ventricle, testis, small intestine, or pancreas. When expressed per gram tissue wet weight, angiotensinogen mRNA levels of extrahepatic tissues were less than 4% of hepatic levels. However, when expressed per milligram total RNA, angiotensinogen mRNA levels of brain, spinal cord, aorta, and mesentery were 26-42% of hepatic levels. Regulation of angiotensinogen mRNA levels was tissue specific. This demonstration of a widespread tissue distribution of angiotensinogen mRNA may indicate a similarly widespread distribution of local angiotensin systems that are independent of the circulating renin-angiotensin system.
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PMID:Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat. 301 40

In vivo generation of angiotensins depends upon both plasma renin and angiotensinogen concentrations. Those factors which may influence hepatic angiotensinogen synthesis and release were examined. We have evaluated in vivo the effects of converting enzyme inhibition on several plasma renin-angiotensin system components, and, using an in vitro preparation of liver slices, we also investigated the effects of converting enzyme inhibition on the synthesis and release of hepatic angiotensinogen. Angiotensinogen concentrations were determined by two different methods. The first was an indirect enzymatic assay which measures the amount of angiotensin I liberated from plasma by an excess of renin. The second was a direct RIA that measures both angiotensinogen and its inactive residue the des-angiotensin I-angiotensinogen. The difference between the methods represents the circulating levels of des-angiotensin I-angiotensinogen. Captopril administration in sodium-depleted rats increased plasma concentrations of renin, des-angiotensin I-angiotensinogen, and angiotensin I and decreased plasma angiotensinogen concentration measured by both methods. Plasma des-angiotensin I-angiotensinogen was significantly correlated to plasma renin concentration, which suggests an increase in the consumption of angiotensinogen when the renin secretion is extremely increased. The angiotensinogen liver content and in vitro angiotensinogen release were decreased in sodium-depleted rats treated with a converting enzyme inhibitor, and these parameters were negatively correlated to in vivo plasma levels of renin, angiotensin I, and des-angiotensin I-angiotensinogen. They were positively correlated to plasma angiotensinogen concentration measured by the indirect assay. These data suggest that captopril administration during sodium depletion has two simultaneous effects: it increases angiotensinogen consumption and second, decreases angiotensinogen production and release.
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PMID:Liver angiotensinogen synthesis and release during captopril treatment in sodium-depleted rats. 303 Jun 98

Arterial blood pressure, renal function and plasma concentrations of renin and renin substrate (angiotensinogen) were investigated in guinea pigs subjected to galactosamine-induced (1 g/kg i.v.) liver cell necrosis. Blood pressure declined continuously by 50% during a follow-up period of 72 h which was associated with a decrease in diuresis and natriuresis to 36 and 31%, respectively. Simultaneously, plasma renin concentration increased 30-fold indicating marked reduction of renal perfusion, while plasma renin substrate concentration fell to 6% of the baseline level. There was microscopic evidence of oligemic circulatory renal damage characterized by acute proximal tubular necrosis with concomitant tubular dilatation. Short-term infusion of homologous renin substrate-enriched plasma, derived from nephrectomized animals, was followed by marked increase in mean arterial blood pressure from 34 +/- 9 to 77 +/- 7 mm Hg accompanied by marked diuresis and natriuresis. Renin substrate depletion following galactosamine-induced fulminant liver failure may represent impaired hepatic biosynthesis as well as increased renin substrate consumption due to excessive renin secretion. Angiotensinogen repletion has a beneficial effect on both renal function and blood pressure probably due to marked generation of the potent vasoconstrictor angiotensin II which consequently inhibits renin secretion. These observations strongly support the suggestion that the renin-angiotensin system is of major importance to cardiovascular homeostasis in acute liver failure.
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PMID:Renin-angiotensin system, blood pressure homeostasis and renal function in galactosamine-induced fulminant hepatic failure in the guinea pig. 304 50

A comparative immunocytochemical and electron microscopic study was performed on renal biopsies from two children with classical Bartter's syndrome (BS) and three children with a recently described variant, the so-called hyperprostaglandin E-syndrome (HES). Compared to age-matched controls, kidney specimens from patients with BS and HES disclosed a marked hypertrophy and hyperplasia of the juxtaglomerular apparatus (JGA). In addition, in HES focal tubular and interstitial calcifications accompanied by interstitial fibrosis and tubular atrophy were noted. On immunocytochemistry, chronic stimulation of the JGA in BS and HES was characterized by an increase in the number of renin-positive cells, particularly in the media of afferent arterioles, but also in efferent arterioles and in the glomerular stalk. The length of the renin-positive portion of the preglomerular arterioles was significantly increased when compared to controls (100 +/- 32 vs. 49 +/- 17 microns; p less than 0.001). In addition, the immunoreactivity of individual renin-positive cells was markedly enhanced. On electron microscopy, "hypertrophy" of the RER and of Golgi complexes with paracrystalline deposits in dilated RER cisterns and protogranules indicated an increased renin synthesis. Renin could be identified in mature secretory granules as well as protogranules by immune electron microscopy. Angiotensinogen was present in hypertrophied epithelial cells of Bowman's capsule. Converting-enzyme reactivity was observed in controls as well as in BS and HES in the brush border of the proximal tubule. In contrast to previous reports, Angiotensin II was completely negative in control as well as in diseased kidneys. We conclude from our results that both BS and HES are characterized by a marked activation of the JGA and severe stimulation of the renin-angiotensin system. Since activation of this system, however, leads--independently of the primary stimulus--to qualitatively very similar morphological reactions, these results do not implicate a common pathogenetic mechanism to both conditions.
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PMID:The juxtaglomerular apparatus in Bartter's syndrome and related tubulopathies. An immunocytochemical and electron microscopic study. 312 15

The antihypertensive effects of 2 different peptidic substrate analogs: AG 84-10 AG 85-12 were investigated in renovascular hypertensive (Goldblatt, 2 kidneys--1 clip) Sprague-Dawley male rats. AG 84-10 (Ac-Pro-Phe-His-Leu-Val-Tyr) is similar to Angiotensinogen 6-13 and AG 85-12 (Ac-Ile-His-Pro-Phe-His-Leu) mimics the C-terminal portion of Angiotensin I. 6 weeks after clipping, hemodynamic profiles of these molecules [Heart rate (HR), mean arterial pressure (MAP), filling parameters, peripheral vascular resistances (PR) and cardiac output (CO)] during 90 minutes, were determined in the anesthetized animals. CO was measured using a thermodilution technique. Parallel radio-immunologic dosages of plasma renin activity were performed. Measurements and calculation of previously defined hemodynamic variables, every 10 minutes, demonstrated that: AG 84-10 exerted an early but transient decrease of MAP and PR, an increase of CO without modification of other hemodynamic parameters. AG 85-12 induced a late and durable decrease of MAP and PR with a significant decrease of heart rate, but without modification of CO and other hemodynamic variables. Example: PR mmHg/ml/mn/kg (mean +/- SD): *p less than 0.05 ** p less than 0.01. (Table: see text). The different levels of plasma renin activity were in accordance with hemodynamic data. So, the 2 peptidic substrate analogs elicited antihypertensive effects with a more efficient action of AG 85-12.
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PMID:[Cardiovascular effects of peptide inhibitors of the renin-substrate reaction in rats with renovascular hypertension. Goldblatt: 2 kidneys--1 clip]. 314 5

It has been proposed that feedback by angiotensin II, the effector peptide of the renin-angiotensin system stimulates hepatic angiotensinogen synthesis, since long-term infusion of this octapeptide in vivo induced an increase in plasma angiotensinogen concentrations. In the present study, the effects of angiotensin II (9 and 90 nmol/l) on angiotensinogen messenger (m)RNA concentrations and on angiotensinogen secretion of freshly isolated rat hepatocytes were compared with those of glucocorticoids (hydrocortisone, 10(-4) mol/l, and dexamethasone, 10(-5) mol/l). Angiotensin II and the glucocorticoids elevated angiotensinogen mRNA concentrations two- to threefold. Angiotensinogen secretion rates were correspondingly increased with a time lag of about 2 h. Differences in the time-course of changes in mRNA following onset or decay of the hormonal effect suggest that angiotensin II and glucocorticoids express their effects by different intracellular mechanisms. This view is supported by the observation that angiotensin II but not dexamethasone has a stabilizing effect on angiotensinogen mRNA, when further synthesis was blocked by actinomycin D.
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PMID:Angiotensin II controls angiotensinogen secretion at a pretranslational level. 324 Dec 34

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.
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PMID:Differential effects of inflammation models on rat T-kininogen and rat angiotensinogen. 328 77

A highly stereoselective synthesis of 2(R)-[5(R)-[1(S)-[(tert-butyloxycarbonyl)amino]-3-methylbutyl]-2,2- dimethyl-4(R)-dioxolanyl]-3-methylbutanoic acid is described. This is a suitably protected carboxylic acid useful as an intermediate for the preparation of renin inhibitory peptides. Angiotensinogen analogues such as peptides IX and X that contain the dipeptide isostere (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid residue at the scissile site are shown to be potent inhibitors of human plasma renin. The glycol moiety in this novel acid, dihydroxyethylene isostere, is suggested to act as a transition-state analogue and mimics the tetrahedral intermediate formed during the enzyme-catalyzed hydrolysis of the peptidic bond.
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PMID:Renin inhibitors. Design of angiotensinogen transition-state analogues containing novel. (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid. 329 39

The renin-angiotensin system is an important regulator of blood pressure and volume homeostasis in mammals. Angiotensinogen, a precursor of the octapeptide angiotensin II and an effector of the renin-angiotensin system, is synthesized in numerous rat tissues. Angiotensinogen is expressed in an islet cell line (RIN 1056A) derived from a rat pancreatic tumor. Angiotensinogen mRNA detected by Northern analysis is abundant in the cell line and is approximately 200 bases longer than the mRNA isolated from rat liver, due to both a longer poly(A) tract and the use of a second polyadenylation site. Dexamethasone is a potent inducer of angiotensinogen mRNA, producing a progressive accumulation from 3 to 96 hr in culture (9-fold above control levels). The dexamethasone effect is competitively inhibited by the glucocorticoid antagonist RU486, and transcription rate assays using isolated nuclei indicate that the effect is primarily at the transcriptional level.
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PMID:Glucocorticoid and thyroid hormone regulation of angiotensinogen gene expression in a pancreatic islet cell line. 329 83


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