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)

The present study was designed to study the functional properties of Angiotensin II (Ang II) binding sites in vascular smooth muscle cells in the Milan hypertensive rat (MHS), a model of low renin hypertension. Smooth muscle cells from MHS rats exhibited increased growth in culture in comparison with the Milan normotensive strain (MNS) as determined by population doubling times (24.5 +/- 2 and 34.8 +/- 2 hours, n = 4, respectively). Hormone receptor number, evaluated by binding assays using [125I]Ang II, showed no difference in either receptor number or affinity for both cell types. The functional responsiveness of Ang II receptors was evaluated by measuring the activation of phospholipase C, Na(+)-H+ exchange, and cytosolic Ca2+ levels. Phospholipase C activity was determined as tritium-labeled inositol trisphosphate and bisphosphate release before and after 15-second exposure to 10(-7) M Ang II. Ang II-stimulated phospholipase C activity in MNS (p less than 0.02) but not in MHS cells. Na(+)-H+ exchange was measured as the dimethylamiloride-sensitive 22Na+ influx into acid-loaded vascular smooth muscle cells with and without 10(-7) M Ang II. In MNS cells, Ang II significantly stimulated (p less than 0.001) antiporter activity but not in MHS cells, which showed a uniformly blunted response. MHS cells exhibited higher basal cytosolic Ca2+ levels than MNS cells, but Ca2+ rapidly increased in the presence of Ang II in MNS but not in MHS cells. Direct activation of phospholipase C by GTP-gamma-S in permeabilized cells indicated that both strains exhibited similar coupling levels by guanine-nucleotide binding proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular smooth muscle cells from the Milan hypertensive rat exhibit decreased functional angiotensin II receptors. 234 21

Collagenase dispersion of rabbit kidney cortex followed by centrifugation on discontinuous sucrose gradient, allowed the simultaneous obtention of microvascular, glomerular and tubular fractions. Microscopic studies and the measurements of cellular renin activity and the muscle-specific-enzyme creatine kinase showed that these vessels were arteriolar in nature and that they contained the preglomerular arterioles. The glomerular or tubular contamination rates were assessed by means of enzymatic markers. AVP stimulated only the tubular fraction whether GTP was present or not. In the absence of GTP, beta-isoproterenol stimulated only the tubular enzyme while in the presence of GTP, the microvascular and especially the glomerular AC were also stimulated. GTP enhanced considerably the microvascular response to bPTH-(1-34) while, in the glomeruli and tubules the effects of GTP and hormones were only additive. The possible physiological significance of these results are discussed.
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PMID:[Distribution of various sites of hormonal action between microvessels, glomeruli and tubules isolated from the renal cortex of rabbits]. 608 66

The properties of renin granules isolated from rat renal cortex were studied. Renin granules were thermolabile since in 10 min at 0 degrees C twice as much renin was released as at +37 degrees C. Addition of Ca++ (10(-6) M - 10(-2) M) did not affect the spontaneous release at +37 degrees C, pH 6.5, during 10 or 30 min incubation. However, when pH was elevated to above 7, renin release was significantly increased by Ca++ (10(-3) M). Additions of various amounts of KCl, NaCl or MgCl2, which increased the osmolality less than 20 mOsm/kg, did not affect the stability of the renin granules. Mg-ATP (0.5 and 5 mM) as well as Mg-GTP (5 mM) stabilized renin granules at +37 degrees C, pH 6.5, but the corresponding nitrogen analogues Mg-AMP-PNP and Mg-GMP-PNP (0.5 and 5 mM) were not effective. Neither did Mg-AMP (5 mM) nor ATP (5 mM) without Mg++ affect the renin release. No stabilization was observed by Mg-ATP and Mg-GTP in the purified granule preparations. The results suggest the importance of the cleavage of the terminal phosphate in the stabilization process. When the granules prepared at 300 mOsm/kg were first kept at hyperosmotic medium (range 300-1650 mOsm/kg) and then moved back to 300 mOsm/kg, the granules tend to lyse the more the greater was the reduction of the osmolality. The granules were more stable in isotonic sucrose than in isotonic ionic medium.
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PMID:Further studies on properties of renin granules isolated from rat kidney cortex. 703 14

The association of obesity and hypertension is well documented, and the combination is important as a coronary risk factor, but its non-pharmacological management is very difficult. Japanese hypertensive obese subjects (HO, n = 95) selected from 321 non-medicated obese subjects with a body mass index > 25 kg/m2 were characterized by the clinical features of significant diaphragmatic elevation, higher heart rate (HR), fasting blood glucose (FBS), total cholesterol (Tch), uric acid and gamma GTP values and lower vital capacity (VC) compared to those of normotensive-obese subjects (NO, n = 226) (p < 0.01). During a diet therapy program (about 1,200 kcal/day) for HO (n = 55), 25 subjects were treated with a non-drug-dependent pulse-synchronized transpercutaneous electric abdominal muscle stimulator (PEM) (ca. 30,000 muscle contractions/day) for 4 weeks. These subjects showed significant improvement with reduction in body weight (9.4%, 7.4 kg), intra-abdominal visceral fat (VF) CT scan area (29%), abdominal subcutaneous area (10%) at the level of the umbilicus, blood pressure (BP), HR, FBS, gamma GTP, Tch, plasma norepinephrine, plasma renin activity and plasma insulin, an increase of VC and lowering of the diaphragm (p < 0.05). The reductions in weight, BP, FBS and Tch in the diet group (n = 30, 1,200 kcal/day for 4 weeks) were smaller than those in the PEM-diet group (p < 0.05). The Japanese hypertensive obese patients had complications of many other coronary risk factors, and the reduction in weight and VF with PEM-diet therapy seems to be effective for improving these risk factors.
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PMID:Improvement of multiple coronary risk factors in obese hypertensives by reduction of intra-abdominal visceral fat. 789 17

There are two major isoforms of the angiotensin II receptor, type 1 (AT1) and type 2 (AT2). AT2 is distinguished from AT1 with respect to its ligand selectivity, its insensitivity to non-hydrolyzable GTP analogues, and its as yet unidentified biological functions. In the present study we have expression-cloned AT2 cDNA from a cDNA library of a rat pheochromocytoma cell line (PC12w). Rat AT2 cDNA encodes a 363-amino acid protein that has seven transmembrane domains. AT1 is the closest in homology to AT2 but with only a 32% identity of amino acid sequence. Stably expressed in COS-7 cells, the receptor showed selective binding to AT2-specific ligands PD123319 and CGP42112A but not to the AT1-specific ligand, losartan. Northern blot analysis revealed that the mRNA of rat AT2 was expressed not only in PC12w cells but also in the adrenal glands and in the inferior olive of the brain, both of which are known to contain AT2 type binding sites. The expressed AT2 receptor mediated angiotensin II-induced inhibition of protein tyrosine phosphatase, an action that was dependent on a pertussis toxin-sensitive G-protein-coupled mechanism in COS-7 cells. The AT2-specific ligand CGP42112A was an agonist rather than antagonist in the inhibition of phosphotyrosine phosphatase. AT2 did not cause a decrease in cGMP in PC12w or COS-7 cells expressing AT2 stably. These results indicate that the AT2 receptor is structurally and functionally different from AT1 and suggest novel functional roles of the renin-angiotensin system in cross-talk with phosphotyrosine signaling by modulating protein phosphotyrosine levels.
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PMID:Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. 822 11

Angiotensin II is the major effector peptide of the renin-angiotensin system, and it exerts its physiologic functions via a G protein-coupled cell surface receptor called AT1. We found that in rat aortic smooth muscle cells, angiotensin II stimulated the formation of Ras-GTP, Ras-Raf-1 complex formation, and the tyrosine phosphorylation of two important Ras GTPase-activating proteins (GAPs), p120 Ras-GAP and p190 Rho-GAP. Electroporation of anti-pp60c-src antibody into cultured, adherent smooth muscle cells blocked the angiotensin II stimulation of Ras-GAP and Rho-GAP tyrosine phosphorylation. In contrast electroporation of antibodies against c-Yes or c-Fyn had no effect. Anti-pp60c-src antibody also blocked angiotensin II-stimulated Ras activation and Ras-Raf-1 complex formation. These data strongly suggest that a G protein-coupled receptor such as the AT1 receptor can activate the Ras protein cascade via the tyrosine kinase pp60c-src.
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PMID:Angiotensin II controls p21ras activity via pp60c-src. 862 2

125I-labeled rat amylin binds to specific sites in the cortex of rat kidney, which can be distinguished from those for 125I-labeled salmon calcitonin (sCT) and 125I-labeled rat alpha-calcitonin gene-related peptide (alpha-CGRP) on the basis of regional distribution. These sites have a high affinity (approximately 1 nM) for amylin, and 125I-amylin binding is potently inhibited by the peptide antagonists AC413 and sCT-(8-32), whereas CGRP-(8-37) is a poor inhibitor of binding. Furthermore, incubation with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) inhibits 125I-amylin binding by > 90%, indicating that binding is dependent on coupling to G proteins. In renal cortex, amylin stimulated adenylyl cyclase activity three- to fourfold, and this was inhibited by AC413 and sCT-(8-32) but not by CGRP-(8-37). Amylin activated plasma renin twofold, and this was blunted by prior administration of AC413 but not CGRP-(8-37). We speculate that amylin may play an important role in renal physiology and that in states of hyperamylinemia, as found in obesity and the insulin resistance syndrome, this peptide may be involved in the genesis and development of hypertension.
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PMID:Amylin binding in rat renal cortex, stimulation of adenylyl cyclase, and activation of plasma renin. 877 89

Congestive heart failure (CHF) patients share several similar features, such as reduced cardiac contractility and neurohumoral activation to compensate the impaired cardiac function. In CHF patients, the cardiac renin-angitensin (RA) system, receptors, GTP-binding proteins, and their effector molecules are inevitably exposed to chronically elevated neurohumoral stimulation. A widely recognized concept is that a chronic increase in such stimulation can desensitize target cell receptors and the post-receptor signal transducing pathway. Recently, reports of several studies have indicated that the inhibitory GTP-binding protein (Gi) can be increased in CHF patients and animal models. Although direct evidence for a change in catalytic protein of adenylyl cyclase has not been found, limited information has suggested a reduced catalytic activity in terminally failing hearts. In this paper, we have assessed the changes in beta AR, GTP-binding protein, catalytic protein and beta ARK. We also examined angiotensinogen mRNA expression in failing heart. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies revealed a stronger reaction in the endocardial layer of the human left ventricle than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. In the non-diseased heart, ACE and AT1 receptor RNA are present in ventricular muscles. Renin and Ao mRNA could not be detected in the subendocardium of non-diseased left ventricle, but both were present in the left ventricle of diseased hearts. These data indicate that the cardiac RA system plays an important role in the deterioration of cardiac function.
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PMID:Alterations of signal transduction system in heart failure. 929 May 67

Renin-binding protein (RnBP) is an endogenous renin inhibitor originally isolated from porcine kidney as a complex of renin, so-called high molecular weight (HMW) renin. Our recent studies demonstrated that human RnBP is the enzyme N-acetyl-D-glucosamine (GlcNAc) 2-epimerase [Takahashi, S. et al. (1999) J. Biochem. 125, 348-353]. We have purified recombinant human, rat, and porcine RnBPs expressed in Escherichia coli JM 109 cells. The purified recombinant RnBPs existed as dimers and inhibited porcine renin activity strongly. On the other hand, porcine renin inhibited recombinant GlcNAc 2-epimerase activities. The human GlcNAc 2-epimerase activity could not be detected in the absence of a nucleotide, whereas ATP, dATP, ddATP, ADP, and GTP enhanced the human GlcNAc 2-epimerase activity. Other nucleotides had no effect on human GlcNAc 2-epimerase activity. Rat and porcine GlcNAc 2-epimerases were activated by several nucleotides. Nucleotides that enhance the activity of GlcNAc 2-epimerases protect these enzymes against degradation by thermolysin. These results indicate that mammalian RnBPs have GlcNAc 2-epimerase activity and that nucleotides are essential for formation of the catalytic domain of the enzyme.
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PMID:Effects of nucleotides on N-acetyl-d-glucosamine 2-epimerases (renin-binding proteins): comparative biochemical studies. 1172 82

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.
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PMID:Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction. 1676 97


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