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 interaction between moderate salt depletion and urinary excretions of prostanoids (PGE2,6-keto-PGF1 alpha and TxB2), as well as the effective role of the activated renin-angiotensin system (RAS), in the control of renal function and urinary prostanoid excretions have been investigated in healthy women. Salt depletion (SD, n = 8) was induced by low sodium chloride dietary intake (< or = 60 mmol per day) and combined treatment with natriuretic and potassium sparing drugs. The cumulative sodium deficit was 381 +/- 55 mmol. The renal function and urinary excretion of prostanoids were evaluated during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis (lysine-8-vasopressin (LVP) low-dose infusion). Basal plasma renin activity (PRA) and urinary aldosterone excretion were determined, before the water load, in both the SD group and control studies in normal balance of sodium and potassium (N, n = 20). Paired studies were performed in the absence and in the presence of enalapril in the same SD group, as well as in a subgroup, with normal sodium and potassium balance, previously studied (N3, n = 6). In the SD vs. N group, significantly higher values of PRA and urinary aldosterone excretion were found. The renal antinatriuretic mechanism was activated and the diuretic response to water load depressed. During polyuria, the urinary 6-keto-PGF1 alpha and TxB2 excretions were significantly higher, probably reflecting an increase in the renal synthesis of their precursors. During the late LVP infusion, the urinary PGE2 excretion was also significantly increased, in absence of significant differences in urinary flow rate. In both SD and N3 groups, enalapril decreased the mean arterial pressure (MAP). Despite the decrease in MAP, not significantly different in SD vs. N3 group, the drug did not significantly affect the creatinine clearance. Also, the urinary prostanoid excretions were not significantly affected by enalapril. However, in the SD group, but not in the N3 group, the drug was effective in significantly decreasing the absolute and fractional excretions of sodium and chloride. Moreover, the plasma potassium concentration significantly decreased, despite the concurrent decrease in urinary potassium excretion. The data suggest that: (1) in salt depletion, the prostanoid release from the renal cortical structures was stimulated; (2) the renal prostanoid synthesis, either activated (sodium depletion) or not (normal sodium and potassium balance), was not affected by the RAS pharmacological blockade in the short-term; (3) in salt depletion, the RAS blockade recruited a homeostatic mechanism responsible for the improved renal salt conservation, as well as for the redistribution of potassium between the extra- and intra-cellular compartments.
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PMID:Effective role of the renin-angiotensin system in the control of prostanoid synthesis and renal function in healthy women with moderate salt depletion. 886 76

Low renin hypertension (LRH), which accounts for 10-20% of patients with idiopathic "essential" hypertension, bears hormonal similarities to mineralocorticoid-induced hypertension, but elevated mineralocorticoid concentrations have not been found. Some patients with LRH have normal, rather than suppressed, plasma aldosterone concentrations, so that the ratio of aldosterone concentration to PRA (Aldo/PRA) is high, suggesting inappropriately increased aldosterone biosynthesis. We characterized the CYP11B2 gene that encodes the aldosterone synthase, P450c11AS, in hypertensive and control populations in a single clinic in Santiago, Chile. We directly sequenced the entire CYP11B2 gene in 12 patients with LRH, 2 high renin hypertensive controls, and 2 normotensive controls. All sequences were identical, except that 8 of 24 LRH alleles encoded arginine rather than lysine at position 173. The Arg173 and Lys173 variants were expressed in transfected MA-10 cells, and their ability to convert deoxycorticosterone to aldosterone was measured; the apparent Michaelis constant (Km) for Lys173 was 2.73 mumol/L; the Km for Arg173 was 2.53 mumol/L. The apparent maximal velocity (Vmax) for Lys173 was 6.5 x 10(-3) micrograms/mL.24 h; the Vmax for Arg173 was 7.8 x 10(-3) micrograms/mL.24 h. The first order rate constant, Vmax/Km was 2.38 for Lys173 and 3.08 for Arg173. As these values were not significantly different, we sought to determine whether Arg173 is a polymorphism linked to LRH. We examined position 173 in 52 unselected patients with idiopathic hypertension and 55 normotensive controls by PCR amplification of CYP11B2 exons 3-5 followed by digestion with Bsu361, which digests the Arg173 sequence, but not the Lys173 sequence. More of the hypertensive alleles (39 of 104, 37.5%) than normotensive alleles (25 of 110, 22.5%) carried Arg173 (chi 2 = 5.57; P < 0.02). Most of the Arg173 alleles (31 of 72, 43.1%) were from hypertensive patients with Aldo/PRA below 30, whereas only 5 of 24 (20.8%) Arg173 alleles were found in patients with Aldo/PRA greater than 30 (chi 2 = 3.79; P = 0.05) Thus, the ARg173 variant of CYP11B2 may be linked to LRH in Chilean patients.
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PMID:Genetic variation in P450c11AS in Chilean patients with low renin hypertension. 895 40

The influence of common salt (NaCl) and a novel potassium-, magnesium-, and L-lysine-enriched mineral salt on the cardiovascular and renal effects of the selective imidazoline I1-receptor agonist moxonidine was examined in spontaneously hypertensive rats (SHR). Common salt was added at the level of 6% of the dry weight of the chow, and mineral salt at a 75% higher level of 10.5% thereof to produce the same NaCl concentration of 6% as in the common salt group. During the control diet an 8-week oral treatment with moxonidine (117 mg/1000 g of the dry weight of the chow producing an approximate daily dose of 10 mg/kg), lowered blood pressure by 13 mmHg. The common salt diet alone raised blood pressure by 27 mmHg. Moxonidine lowered blood pressure by 21 mmHg during the common salt diet, but the blood pressure remained 19 mmHg higher than in the moxonidine-treated SHR receiving the control diet (P<0.05). Unlike common salt, mineral salt alone did not raise blood pressure nor did it interfere with the antihypertensive effect of moxonidine. Moxonidine showed a kidney-protective effect during the control diet measured as decreased urinary protein excretion, but it did not affect the development of left ventricular hypertrophy. Moxonidine increased plasma renin activity during the control diet and it raised the serum aldosterone level both during the control and mineral salt diets. The vascular relaxation responses of the mesenteric arterial rings to both acetylcholine (an indicator of endothelium-dependent vascular relaxation) and nitroprusside and nitroprusside (an indicator of endothelium-independent vascular relaxation) were attenuated by the common salt diet alone but maintained during the moxonidine treatment. Our findings are consistent with the concept that moxonidine is able to improve the excretion of sodium. This effect might explain the maintenance of normal vascular relaxation during a high intake of common salt. These effects may partly account for the antihypertensive effect of moxonidine.
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PMID:Influence of different dietary salts on the cardiovascular and renal effects of moxonidine in spontaneously hypertensive rats. 922 97

Using a cyclolinopeptide A analogue, the hydrophobic cyclic peptide c(-Ala-Lys-Pro-Phe-Phe-Ala-Lys-Pro-Phe-Phe-), termed CDP (cyclodecapeptide), as ligand in affinity chromatography, hepatocellular peptide binding proteins were isolated from the integral part of plasma membranes and the cytosol. The sequence of the isolated protein with MW of 50 kDa from the integral part of the plasma membrane fraction was identical to cytochrome P450 II C13 and cytochrome P450 II C22, whereas the sequence of the 54 kDa protein was identical to 3-hydroxyandrogen-UDP-glucuronosyltransferase. These proteins have also been described as binding proteins for bile acids. As shown in earlier studies, bile acids and CDP also compete for uptake into hepatocytes. In the cytosol, a further known bile acid binding protein, the glutathione-S-transferase (G-S-T) subunit Yb1, was isolated and sequenced as binding protein for CDP and also for a further cyclopeptide, the somatostatin analogue OO8, and a linear peptide with renin-inhibiting activity, EMD 55068. As shown in uptake studies using isolated basolateral plasma membrane vesicles, G-S-T was able to increase the uptake of EMD 51921, a linear peptide with renin-inhibiting potency, into the vesicles when the latter were preloaded with G-S-T. The binding of the substrate to the outside of the preloaded vesicles was not different than binding to unloaded vesicles. The maximal transport rate of the carrier-mediated/facilitated diffusion and the rate of permeation, however, were doubled in the presence of G-S-T, pointing to the involvement of intracellular binding proteins such as G-S-T in the unloading of the carrier protein and in the reduction of the free substrate concentration.
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PMID:Binding proteins for cyclic and linear oligopeptides in plasma membranes and the cytosol of rat hepatocytes. 931 75

1 In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg(-1) day(-1) in the food) and a calcium channel blocker felodipine (0.4 mg kg(-1) day(-1) subcutaneously via an osmotic minipump). 2 Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. 3 The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. 4 Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the alpha-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet. 5 Ramipril and felodipine in combination increased plasma renin activity by 1.9-3.2 fold without affecting serum aldosterone levels. 6 Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium-dependent and endothelium-independent vascular relaxation responses and attenuated alpha-adrenoceptor-mediated vascular contractile responses.
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PMID:Influence of dietary salts on the cardiovascular effects of low-dose combination of ramipril and felodipine in spontaneously hypertensive rats. 948 6

Four members of the tissue kallikrein family, mK1, mK9, mK13, and mK22, all of which exhibit extensive homology in amino acid sequence among themselves, were obtained from the submandibular gland of ICR mice and examined for their ability to cleave prorenin. Tissue kallikrein mK13 was confirmed to be a prorenin-converting enzyme; and mK9, which was earlier shown to be an EGF-binding protein, was found to cleave mouse Ren 2 prorenin specifically and convert it to mature renin with an activity of approximately 1/10 of that of mK13. With the same substrate, mK22 (beta-NGF endopeptidase) gave two products, renin and arginyl-renin; whereas mK1 (true tissue kallikrein) did not process it at all. The endoproteolytic activity of tissue kallikreins was examined with various peptide-MCA substrates. The substrates contained three key structures; X(Y)-Arg-Arg, X(Y)-Lys-Arg and X-Lys-Lys motifs (where X and Y are hydrophilic and hydrophobic amino acids, respectively). We found that mK1, mK9 and mK13 preferentially cleaved the former two types of substrate, except Y-Arg-Arg-MCA. The substrate X-Lys-Lys-MCA was hardly cleaved by these three tissue kallikreins but was preferentially cleaved by mK22. The four tissue kallikreins seem to have the ability to process precursor proteins containing a pair of basic amino acid residues; the specificities of three of the enzymes (mK1, mK9 and mK13) were similar to each other but were different from that of mK22.
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PMID:Prorenin processing and restricted endoproteolysis by mouse tissue kallikrein family enzymes (mK1, mK9, mK13, and mK22). 950 64

The substrate specificities and kinetic properties of proteinase A, an intracellular aspartic proteinase from the yeast Saccharomyces cerevisiae, were determined using a series of synthetic chromogenic peptides with the general structure P5-P4-P3-P2-Phe-(NO2)Phe-P2'-P3' [P5, P4, P3, P2, P2', P3' are various amino acids; (NO2)Phe is p-nitro-L-phenylalanine]. The nature of the residues occupying the NH2-terminal region of the substrate had a strong influence on the kinetic constants. Among those tested, Ala-Pro-Ala-Lys-Phe-(NO2)-Phe-Arg-Leu had the best kinetic constants (Km = 0.012 mM, kcat = 14.4 s-1, kcat/Km = 1,200 M-1.s-1). Compared with such aspartic proteinases as pepsin, cathepsin D, and renin, the substrate specificity of proteinase A was unique. Based on these results, a novel fluorescent substrate, MOCAc-Ala-Pro-Ala-Lys-Phe-Phe-Arg-Leu-Lys(Dnp)-NH2, was developed for the sensitive measurement of proteinase A.
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PMID:Substrate specificities and kinetic properties of proteinase A from the yeast Saccharomyces cerevisiae and the development of a novel substrate. 964 56

Molecular cloning of a cDNA for a pepsin inhibitor in the round worm, Ascaris suum, was achieved. The ORF was found to encode a 20-residue potential signal peptide and a 149-residue inhibitor moiety. Northern analysis showed the mRNA for the inhibitor to be expressed in the body wall and not in the viscera. To obtain the active inhibitor, we constructed a yeast expression vector, pYES2API, containing the inducible galactosidase promoter and a DNA fragment encoding a fusion protein of the yeast alpha-factor leader and the Ascaris pepsin inhibitor. The active inhibitor was secreted in the culture medium, the yield being approximately 3 mg x l(-1) x day(-1), and purified by a two-step procedure that included HPLC. The inhibitor inactivated pepsin A and cathepsin E almost completely at amounts equimolar with the enzymes, but was 100-fold less effective against pepsin C and did not act on cathepsin D and renin. Ki values for the inhibition of pepsin A and cathepsin E were in the nanomolar range below pH 5. Since the inhibitor activity was lost by modification of specific Lys residues, including Lys110, an electrostatic interaction between these Lys residues and Asp/Glu residues of pepsin A or cathepsin E was thought to be essential for the inhibition.
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PMID:Molecular cloning, expression and characterization of an Ascaris inhibitor for pepsin and cathepsin E. 965 82

The first child of consanguineous parents presented with failure to thrive and feeding problems at age 6 weeks. Important laboratory findings were low plasma sodium and elevated potassium and renin. Salt wasting was caused by an enzymatic defect in the terminal aldosterone biosynthesis. The biochemical diagnosis of corticosterone methyloxidase (CMO) deficiency type II was established on the basis of plasma multisteroid analysis, showing a pathologic increase of 18-OH-corticosterone/aldosterone ratio. Sequence analysis of the CYP11B2 gene which encodes aldosterone synthase (P450c11Aldo), the enzyme required for the terminal steps in aldosterone biosynthesis, revealed a hitherto undescribed homozygous deletion of codon 173. CYP11B2 is polymorphic at this position, encoding arginine or lysine. Both parents were heterozygous carriers of the mutation. Amino acid residue 173 in P450c11Aldo is positioned in alpha-helix D. We presume that the secondary structure of the enzyme is changed by the single amino acid deletion. This report describes a novel mutation in the CYP11B2 gene, the third known mutation associated with CMO deficiency type II.
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PMID:Homozygous deletion of arginine-173 in the CYP11B2 gene in a girl with congenital hypoaldosteronism. Corticosterone methyloxidase deficiency type II. 983 44

Renin, which catalyzes the initial proteolytic cleavage reaction in the production of angiotensins, is first synthesized as a zymogen, prorenin, and requires the proteolytic removal of an amino-terminal prosegment for activation in vivo. The lysosomal hydrolase cathepsin B has been proposed as a prorenin processing enzyme based on reports of its co-localization with renin in the secretory granules of certain tissues and its ability to activate prorenin in vitro. In the current study, scanning mutagenesis was used to identify the amino acids which determine the site selectivity of prorenin cleavage by human cathepsin B in vitro. Co-expression assays in AtT-20 cells were also used to test for the ability of cathepsin B to cleave human prorenin within cells. Our results suggest that a basic lysine residue at the -2 position from the cleavage site is required for cathepsin B cleavage of prorenin in vitro and that the structure of prorenin itself may account for the selection of the proper cleavage site. In addition, although cathepsin B appears to be correctly sorted to lysosomes, the enzyme exhibits prorenin processing activity in transfected AtT-20 cells, raising the question of the cellular localization in which the processing event occurs.
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PMID:Prorenin processing by cathepsin B in vitro and in transfected cells. 992 50


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