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)

1. Inactive renin in human plasma can be activated by pH 3.3-dialysis (generation of acid-activated renin), by clotting factor XII-mediated prekallikrein to kallikrein conversion after pH has been restored to neural (generation of acid-kallikrein-activated renin) or by the addition of trypsin (generation of trypsin-activated renin). 2. Natural active renin, acid-kallikrein-activated renin and trypsin-activated renin behave similarly during affinity chromatography on Blue-Sepharose CL-6B and during gel filtration on Sephadex G-100. They also show similar reaction kinetics with similar pH-optimum curves when acting on sheep renin substrate. 3. Acid-activated renin is different. It is retained on Blue-Sepharose columns and it is inactivated at neutral pH during incubation at 37 degrees C. This contrasts with the other forms of renin activated in vitro and with natural active renin. The pH-optimum curve of acid-activated renin, when acting on sheep renin substrate, is also different from that of the other forms of active renin. 4. It is to be proven that the renins generated in vitro by neutral serine proteinases are identical with natural active renin, but clearly they bear more resemblance to natural renin than acid-activated renin does. Our preliminary conclusion is that acid-activated renin is a 'laboratory renin', which does not circulate in normal peripheral venous plasma.
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PMID:Two forms of plasma renin after activation in vitro and their relation to natural plasma renin. 703 18

1. A cDNA clone library was constructed from male mouse submandibular gland poly(A)+RNA. 2. A 500 base-pair sequence consisting of a 3' untranslated region plus a 447 base-pair region coding for an amino acid sequence having 57% homology with the C-terminal 149 amino acids in the 230 amino acid chain of porcine pancreatic kallikrein was identified. 3. The sequence was strongly but not completely homologous with known mouse submandibular gland serine proteinase sequences and represents the first report of a DNA base sequence for a serine proteinase. It may be part of the gene coding for kallikrein. 4. The biosynthetic pathway for renin was established by continuous-labelling, pulse-chase and cell-free translation studies of submandibular gland tissue from normal and testosterone-induced mice. 5. Renin was synthesized as a mol. wt. 46000 preprorenin which is likely to be hydrolysed before completion of the nascent chain. A prorenin of mol. wt. 44500, pI 6.4 was identified and shown to be rapidly converted into a mol. wt. 40000, pI 6.2 renin, which was then converted more slowly into forms of mol. wt 35500, pI 5.6 and mol. wt. 34000, pI 5.4.
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PMID:Kallikrein and renin: molecular biology and biosynthesis. 703 21

Various facets of activation of inactive renin by acidification or cold exposure were investigated in normal human plasma. The acid activation obtained by titration was usually less than that by dialysis method, but varied from 41% to 122% of the latter. The acid phase of acid activation accounted for about 70% of the total activation achieved by the combined effects of the acid and alkaline phases on the average, and was not affected by any of the inhibitors for serine, thiol or carboxyl protease, whereas serine protease inhibitors suppressed the activation of both renin and plasma kallikrein in the alkaline phase of acid activation. A different mode of plasma kallikrein activation suggested some difference in the mechanism between the alkaline phase of acid activation and the cryoactivation. A part of cryoactivation of renin was independent of the action of plasma kallikrein. The renin activated by either acidification or cold exposure without concomitant activation of plasma kallikrein was reinactivated by the removal of pH and temperature, but recovered by repeating acidification or cold exposure. When active plasma kallikrein had been produced, it activated inactive renin irreversibly. It appears unlikely that irreversible activation of inactive renin is taking place in the normal circulation where practically no active plasma kallikrein is present.
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PMID:Activation and reinactivation of inactive renin in normal human plasma. 703 32

Several intervention studies with angiotensin I converting enzyme (ACE) inhibitors have demonstrated a remarkable improvement in the treatment of patients with primary hypertension and congestive heart failure. Since ACE inhibitor therapy in patients with congestive heart failure not only improves systemic haemodynamics but also provides a better prognosis, the cardiac renin-angiotensin system is apparently one of the major targets of ACE inhibitor therapy. Recent studies provided evidence that the human heart contains high affinity Ang II (Ang II) receptors with both subtype population and ACE. In addition to ACE, a novel cardiac Ang II forming enzyme (human chymase) has been identified in human hearts. Unlike in the rat heart, the minor (10%) component of Ang II-forming activity in the left ventricle is due to ACE, whereas the major (80%) component is due to human chymase. This novel cardiac serine proteinase has been purified from the human left ventricle and characterized, and recently, the cDNA and the gene for this enzyme have been cloned. Biochemical characterization revealed that human chymase is the most efficient and specific Ang II-forming enzyme described thus far, but the cellular and regional distribution of the two Ang II-forming enzymes seems to be different. ACE is mainly localized in endothelial cells and fibroblasts and the expression level is higher in atria than ventricles, whereas chymase is synthesized and stored in secretory granules of mast cells, endothelial cells, and mesenchymal cells, and after its secretion localized in the interstitial region of the myocardium and its expression is higher in ventricles than atria. These results imply distinct roles of these two Ang II-forming enzymes in cardiac Ang II formation and in the physiological function of the human heart. Since localization of cardiac renin and angiotensinogen were also identified in human heart, it is important to understand the detailed mechanisms of the tissue Ang II formation and its contribution to the pathophysiological changes in cardiovascular diseases.
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PMID:Tissue angiotensin II system in the human heart. 771 17

Protease nexin-1 (PN-1) is a potent inhibitor of serine proteases, such as thrombin and plasminogen activators, which is secreted into the extracellular space. Since PN-1 is induced following lesion of the sciatic nerve, the effect of substances known to accumulate at the site of injury was examined in primary cultures of Schwann cells. Among the cytokines, growth factors, mitogens, neurotrophins, and neuroactive peptides analyzed, only angiotensin II (Ang II), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were found to regulate the expression of PN-1 on Schwann cells. While Ang II and CGRP caused downregulation, VIP acted as a positive modulator of PN-1. Displacement of Ang II binding using the selective ligands losartan and CGP 42112 led to a severalfold increase of PN-1 protein and mRNA over basal levels, indicating that the observed effect was mediated by specific binding sites. Indeed, the presence of AT1 and AT2 angiotensin receptor subtypes was demonstrated in cultured Schwann cells as well as in the rat sciatic nerve. Moreover, the detection of angiotensinogen- and renin-mRNA in these cultures suggested an endogenous production of Ang II. This data identified one of the mechanisms regulating PN-1 synthesis. Altogether our results indicate that neuropeptides can differentially control the proteolytic activity of the microenvironment, providing new aspects of neuron-glia interactions in the intact tissue and following nerve injury.
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PMID:Regulation of protease nexin-1 expression in cultured Schwann cells is mediated by angiotensin II receptors. 782 77

To study the oxytocic effect of trypsin, we measured the force of isometric contraction in uteri isolated from estrogenized rats exposed to trypsin (8.8 x 10(-10) to 1.7 x 10(-6) mol/L) either alone or in the presence of receptor antagonists to angiotensin II [saralasin ([Sar1,Ala8]angiotensin II) or DuP 753 (losartan)] or to kinins (D-[Arg0,Hyp3,Thi5,8,D-Phe7]-bradykinin). We found that saralasin or DuP 753, but not the kinin antagonist, displaced the dose-response curve to the right. Exposure to exogenous angiotensin I desensitized the preparation to further doses of either angiotensin I or II or trypsin, without altering the effects of oxytocin or bradykinin. Enalaprilat (an angiotensin I converting enzyme inhibitor) or pepstatin A (a renin inhibitor) also displaced the dose-response curve to trypsin to the right, without altering the effects of oxytocin or angiotensin II. Our results indicate that the response to trypsin is mediated by an agent produced from a substrate present in the uterus and acting on the angiotensin II type 1 receptor and are consistent with both renin and angiotensin I converting enzyme being involved in its mechanism of action, thus supporting the notions that the renin-angiotensin system may be important in the late stages of pregnancy and that serine proteases existing in the uterus may contribute to its activation.
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PMID:Oxytocic effect of trypsin on the isolated rat uterus. 828 69

Angiotensin-I converting enzyme (ACE) inhibitors have provided a remarkable improvement in the treatment of patients with primary hypertension and congestive heart failure. The cardiac renin-angiotensin system is one of the major targets of ACE inhibitor therapy since recent studies show that the human heart contains high affinity angiotensin II (Ang II) receptors and ACE activity. However, it is not clear why ACE inhibitors are more effective than other vasodilators in the treatment of patients with congestive heart failure. This gap in knowledge led us to study the biochemical mechanism of Ang II formation in the human heart. Such studies have only recently been addressed. So far, two Ang II-forming enzymes (ACE and human chymase) have been identified. Unlike in the rat heart, the minor (10%) component of Ang II-forming activity in the left ventricle is due to ACE, whereas the major (80%) component is due to human chymase. This novel cardiac serine proteinase has been purified from the human left ventricle and characterized, and recently, the cDNA and the gene for this enzyme have been cloned. Biochemical characterization revealed that human chymase is the most efficient and specific Ang II-forming enzyme described thus far, but the cellular and regional distribution of two Ang II-forming enzymes seem to be quite different. ACE is localized mainly in endothelial cells and its expression level is higher in atria than ventricles whereas chymase is localized in the interstitial region of the myocardium and its expression is higher in ventricles than atria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiac angiotensin II formation: the angiotensin-I converting enzyme and human chymase. 829 72

We have demonstrated that angiotensinogen is synthesized by 3T3-F442A cells and is hydrolyzed to angiotensins I and II (ANG I and II) by this model adipocyte system. This study was designed to determine whether ANG I is generated by renin or some other enzyme and where the formation of ANG I and/or II occurs in 3T3-F442A cells. Renin mRNA was not detected by Northern blot analysis of poly(A)(+)-selected RNA from cultures of fully differentiated adipocytes nor by the more sensitive polymerase chain reaction, implying that renin is not synthesized in this model adipocyte system. Hydrolysis of angiotensinogen to ANG I and II was demonstrated to be associated with the cell but not the media. Inhibitors, including EDTA, aimed at inactivating enzymes belonging to the serine, acid, or aspartyl proteases, and metalloproteases were ineffective in preventing the formation of either ANG I or II. Therefore the model adipocyte 3T3-F442A cell system forms ANG I and II in the absence of renin and angiotensin-converting enzyme. The unidentified enzymes responsible for peptide formation are associated with the cell itself.
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PMID:Localization of angiotensin peptide-forming enzymes of 3T3-F442A adipocytes. 833 6

The cloning of renin, angiotensinogen and angiotensin converting enzyme genes have established a widespread presence of these components of the renin-angiotensin system in multiple tissues. New sites of gene expression and peptide products in different tissues has provided strong evidence for the production of angiotensin independently of the endocrine blood borne system. In addition, the cloning of the angiotensin receptor (AT1) gene has confirmed the widespread distribution of angiotensin and suggested new functions for the peptide. This review of various tissues shows the variation in gene expression between tissues and angiotensin levels, and the fragmentary state of our knowledge in this area. As yet we cannot state that the gene expression of the substrates, enzymes and peptide products are involved in a single cell synthesis. This is not so much evidence against a paracrine function for tissue angiotensin, as lack of detailed, accurate intracellular information. The low abundance of renin in brain, spleen, lung and thymus compared to kidney, adrenal, heart, testes, and submandibular gland may suggest that there are both tissue renin-angiotensin systems (RAS) and nonrenin-angiotensin systems (NRAS). The NRAS could function through cleavage of angiotensinogen by serine proteinases such as tonin and cathepsin G to form Ang II directly. Although much angiotensinogen is extracellular and could therefore be a site of synthesis outside of the cell, intracellular angiotensinogen in a NRAS process could produce Ang II intracellularly without requiring extracellular conversion of Ang I to Ang II by ACE. In summary, renin mRNA is found in high concentrations in kidney, adrenal and testes and decreasing lower concentrations in ovary, liver, brain, spleen, lung and thymus. Angiotensinogen mRNA is found in the following tissues in descending order of abundance: liver, fat cells, brain (glial cells), kidney, ovary, adrenal gland, heart, lung, large intestine and stomach. It is debatable whether angiotensinogen and renin mRNA are expressed in blood vessels. The evidence that is lacking for a paracrine function of angiotensin is a complete description of the intracellular molecular synthesis and release of Ang II from single cells of promising tissues. Such tissues, SMG, ovary, testes, adrenal, pituitary and brain (neurons and glia) are potent sources of RAS components for future studies. Although the evidence for a paracrine function of angiotensin II is incomplete, it is an important concept for progressing toward the understanding of tissue peptide physiology and the significance of their gene regulation.
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PMID:Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. 842 6

The present study was designed to determine the developmental changes in intrarenal angiotensin (Ang) peptides in the rat. Kidney Ang I and II levels were threefold and sixfold higher in newborn than adult kidneys, respectively (Ang I, 678 +/- 180 versus 243 +/- 38 fmol/g, P < .01; Ang II, 667 +/- 75 versus 103 +/- 6 fmol/g, P < .001). Intrarenal Ang II levels correlated positively with the temporal changes in renin gene expression (r = .93, P < .001). However, no correlation was found between renal Ang II content and angiotensin-converting enzyme (ACE) expression during development, which prompted us to evaluate whether renal enzymes, other than renin and ACE, contribute to Ang II formation in the developing kidney. Angiotensin peptide levels were measured in newborn and adult kidney homogenates incubated with human angiotensinogen (a poor rat renin substrate) for 30 minutes at 37 degrees C. Inhibitors of aspartyl proteases and metalloproteases were ineffective in preventing the formation of Ang II in either newborn or adult kidneys. However, addition of the serine protease inhibitors soybean trypsin inhibitor and phenylmethylsulfonyl fluoride inhibited Ang II generation in the newborn kidneys only. In contrast, Ang I generation was not affected by inhibition of serine proteases in either newborn or adult kidneys. We conclude that Ang I and II synthesis is activated in the developing rat kidney. In addition to renin and ACE, the newborn rat kidney expresses serine protease activity that is capable of generating Ang II directly from angiotensinogen. This putative enzyme is induced in the newborn kidney and may cooperate with renin in the activation of Ang II synthesis during early development.
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PMID:Activation of angiotensin-generating systems in the developing rat kidney. 856 53


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