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:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel renin inhibitor, YM-21095 [2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-buthyl]-L- histidil-amino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-but anol), has been synthesized in our laboratories. The aim of this study was to evaluate the pharmacological properties of YM-21095 in in vitro and in vivo experiments. YM-21095 inhibited human renin with an IC50 value of 4.7 x 10(-10) mol/L. YM-21095 was also a potent inhibitor against squirrel monkey renin, but less effective against renins from dog, rabbit, and rat. The effect of YM-21095 is highly specific for renin, since it did not inhibit cathepsin D, pepsin, or angiotensin converting enzyme up to a concentration of 10(-4) mol/L. YM-21095 was resistant to proteolytic actions of the enzymes (pepsin, chymotrypsin, trypsin) and squirrel monkey tissue homogenates (liver, kidney, small intestine). Intravenous infusion of YM-21095 (0.1 to 100 micrograms/kg/min) decreased mean blood pressure and inhibited plasma renin activity in a dose-dependent manner with no effect on heart rate in anesthetized sodium-depleted and sodium-replete squirrel monkeys. The hypotensive effect of YM-21095 in sodium-depleted squirrel monkeys was about ten times as potent as that in sodium-replete squirrel monkeys. Oral administration of YM-21095 to conscious sodium-depleted squirrel monkeys produced dose-related decreases of systolic blood pressure. We conclude that YM-21095 is a potent and highly specific inhibitor of primate renin and produces a blood pressure lowering effect.
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PMID:Pharmacological properties of YM-21095, a potent and highly specific renin inhibitor. 181 49

A 54-year-old woman was referred to our hospital for the treatment of a tumor of the right chest wall. Clinical examination revealed hypertension, hypokalemia, metabolic alkalosis, hyperaldosteronism and hyperreninemia. Computed tomography and an abdominal echogram indicated a tumor in the right phrenic area and two tumors in the retroperitoneum near the pancreas head. After the surgical resection of these tumors, the primary reninism was diminished. The pathological diagnosis of these tumors was leiomyosarcoma. Plasma active and inactive (trypsin-activated) renin activities (PRA) were 85.7 and 38.9 ng angiotensin I/ml/h, respectively. These PRA did not respond to either postural stimulation or suppression by the volume expansion. Active and inactive renin activities in a right phrenic area tumor were 208 and 32 ng angiotensin I/mg protein /h, respectively. Those of an abdominal tumor were 196 and 30 ng angiotensin I/mg protein/h, respectively. Renin mRNA identical in molecular size to that of the human kidney was identified by northern blot analysis. This is the first case report of renin producing leiomyosarcoma derived from the lung, which is characterized by relatively lower plasma prorenin concentrations.
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PMID:A case of renin producing leiomyosarcoma originating in the lung. 182 28

Most mouse inbred strains carry two renin genes, Ren-1 and Ren-2, Renin-2, the product of the Ren-2 gene, is highly expressed in the submaxillary gland. It is a renin isoenzyme 96% similar to kidney renin-1, but unglycosylated. In order to investigate if glycosylation of prorenin affects its processing and/or secretion we have introduced two potential N-linked glycosylation sites into preprorenin-2 cDNA using site-directed mutagenesis. Expression plasmids were derived from wild-type and mutant renin-2 cDNA and were transfected into AtT20 cells. Both transfected cells, expressing glycosylated or unglycosylated forms, secreted prorenin and renin by the constitutive and regulated pathways, respectively. Prorenin was correctly processed to active renin but the second maturation site was not cleaved in AtT20 cells. The comparison of glycosylated and unglycosylated renin expression showed a diminished secretion of glycosylated active renin. Prevention of glycosylation with tunicamycin resulted in an improved secretion of active renin. Moreover, the efficiency of the trypsin activation in vitro was reduced for glycosylated prorenin and it was restored when the activation was performed on mutant renin secreted from tunicamycin-treated cells. It is proposed that the bulky carbohydrates attached to prorenin constitute a steric hindrance to proteolysis by maturation enzymes.
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PMID:N-linked glycosylation affects the processing of mouse submaxillary gland prorenin in transfected AtT20 cells. 190 27

To investigate the enzyme involved in the activation of plasma inactive renin in vivo, we measured the changes in plasma active renin, inactive renin and prekallikrein, and the levels of urinary kallikrein excretion in 10 primary glomerulonephritic patients before and after a low sodium (Na; 17 mEq/day) constant potassium (K; 40 mEq/day) diet for 5 days. Plasma inactive renin was activated by trypsin. Active renin was measured by the amount of angiotensin I generated when sheep substrate was added to the plasma. Plasma prekallikrein was measured by its activity on substrate S-2302 after activation. Urinary kallikrein was measured by its activity on substrate S-2266. The results showed that changes in plasma active renin (7.7 +/- 2.9 to 23.8 +/- 9.9 ng/ml/h), and inactive renin (61.5 +/- 10.2 to 145.7 +/- 53.9 ng/ml/h) and urinary kallikrein excretion (6.7 +/- 1.1 to 10.8 +/- 2.4 nkat) were significant. No significant change in plasma prekallikrein was observed. The correlation between plasma active renin and inactive renin was significant both before and after the low salt diet. The correlation between the ratio of active to total renin and urinary kallikrein was significant before the low salt diet. These results are compatible with the postulate that plasma inactive renin may be a renin precursor, but they do not support the theory that either plasma kallikrein or renal kallikrein is related to activation of inactive renin in vivo.
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PMID:Effect of sodium depletion on active renin, inactive renin and prekallikrein in plasma and urinary kallikrein excretion in glomerulonephritic patients. 197 41

Renin messenger ribonucleic acid expression has been shown in decidual tissue and endometrium, but weakly in chorion laeve, suggesting decidua as a primary source of uteroplacental renin. We proposed to confirm active renin secretion by endometrial stromal cells and examined the effect of progesterone-induced decidualization on secretion. Separate monolayer cultures of endometrial stroma, trophoblast, and mesenchymal cells were established and maintained for 10 to 15 days. Active renin concentration was measured with radioimmunoassay for angiotensin I generation and expressed as picograms per milliliter of angiotensin I generation per 10(5) cells. Active renin concentration was high in control secretory endometrial stromal cells (513 pg/ml) compared with trophoblast (none) and mesenchymal cell cultures (74 pg/ml). Marked decrease in active renin secretion occurred in control endometrial stromal cells (days 13 to 15, 86 pg/ml), whereas progesterone-induced decidualization sustained and increased secretion (days 13 to 15, 1017 pg/ml). This renin activity was quantitatively inhibited in culture fluid assays by specific human renal renin antibody in serial dilutions. Renin activity measurements before and after trypsin activation showed the majority of renin (91.15%) in the inactive form and a smaller fraction (8.85%) in the active form. Immunohistochemistry with the use of specific human renal renin antibody confirmed the presence of renin and its stimulation by progesterone in endometrial stromal cells. Progesterone had minimal effect on mesenchymal cells. These data confirmed endometrial stromal cells as a significant source of active renin and showed that progesterone induced a marked increase in this production.
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PMID:Effect of progesterone on renin secretion in endometrial stromal, chorionic trophoblast, and mesenchymal monolayer cultures. 201 41

Recombinant human prorenin (rh-prorenin) was purified from supernatants of Chinese hamster ovary (CHO) cell line transfected with the cDNA for rh-prorenin by employing a simple two-step procedure which consisted of ammonium sulfate precipitation and immunoaffinity chromatography using a monoclonal antibody specific for the profragment of human prorenin. About 100-fold purification with 35% recovery was achieved after the two steps. Purified rh-prorenin migrated as a single protein band with apparent molecular weights of 46,000-47,000 and about 50,000 on SDS-PAGE and gel filtration (HPLC), respectively, although it consisted of multiple components (pI values, 5.6-6.4) that could be resolved by isoelectric focusing (IEF). The treatment of rh-prorenin with endo-beta-N-acetylglucosaminidase converted the rather broad protein band to a sharp band on SDS-PAGE and reduced the number of multiple pI peaks on IEF. Amino-terminal sequence analysis of both the purified rh-prorenin and rh-renin revealed Leu-Pro-Thr-Asp- and Leu-Thr-Leu-Gly-, respectively, which agreed with those predicted from the base sequences of their cDNA. These data suggested that microheterogeneity of rh-prorenin is due to the carbohydrate moiety, but not to the protein moiety. Purified rh-prorenin was almost inactive, but was cleaved at the carboxyl end of a dibasic pair Lys-2-Arg-1 by trypsin and converted to active renin. However, at the early stage during trypsin activation, new intermediate forms between rh-prorenin and rh-renin were formed, suggesting multiple activation steps of rh-prorenin in addition to the one step activation.
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PMID:Isolation and characterization of recombinant human prorenin in Chinese hamster ovary cells. 201 71

To determine whether or not rat plasma inactive renin is prorenin, specific antibodies were raised against two 15-amino acid peptides, Pro-NH2 and Pro-COOH, which contained the NH2-terminal and COOH-terminal sequences, respectively, of the prosegment of rat prorenin. Inactive renin was measured after trypsin treatment. Immunoaffinity chromatography of normal rat plasma on anti-Pro-NH2 and anti-Pro-COOH immunoglobulin G (IgG)-Sepharose showed that about one-half the amount of inactive renin was prorenin, whereas the rest was neither prorenin nor renin. Thus trypsin treatment of the unfractionated plasma does not provide measurement of the concentration of prorenin. However, fractionation of plasma by high-performance liquid chromatography on G3,000SW columns followed by trypsin treatment led to the measurement of prorenin. Prorenin and active renin concentrations in the normal plasma of conscious rats were 44.3 +/- 5.8 and 13.3 +/- 1.4 (SE) ng ANG I.h-1.ml-1, respectively (n = 10). On the other hand, plasma inactive renin from rats at 24 h after bilateral nephrectomy bound to neither anti-Pro-NH2 nor anti-Pro-COOH IgG immunoaffinity columns, and the enzymatic activity after trypsin treatment was not inhibited by anti-mature renin IgG. These results demonstrate that inactive renin from nephrectomized rats was not prorenin. Thus the kidney is the primary source of circulating prorenin in rats.
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PMID:Immunological evidence that kidney is primary source of circulating inactive prorenin in rats. 201 18

Rat prorenin was synthesized by Chinese-hamster ovary cells transfected with an expression vector containing rat preprorenin cDNA sequences, then purified by concanavalin A-Sepharose chromatography and h.p.l.c. on G3000SW. The molecular mass of purified prorenin was 46,000 Da, as determined by h.p.l.c. on G3000SW. Immunoblot analysis indicated that recombinant prorenin cross-reacted with anti-(mature renin) antibody and two kinds of antibodies recognizing the N-terminus and C-terminus of the prosegment of rat prorenin. Recombinant prorenin was bound to a Cibacron Blue-Sepharose column and eluted with 1.4 M-NaCl, but was not retained by an octapeptide renin inhibitor (H-77)-Sepharose column. Trypsin activation of prorenin increased the renin activity 110-fold, caused binding to an H-77-Sepharose column and nullified the reactivity to the above two kinds of anti-prosegment antibodies, findings indicating that the activation of prorenin with trypsin is due to the cleavage of the prosegment. Rat plasma inactive renin, partially purified by h.p.l.c. on G3000SW, had much the same physicochemical characteristics as the recombinant prorenin. These results provide evidence that rat plasma inactive renin is prorenin. Recombinant prorenin is a useful material for examining the physiological role of circulating prorenin.
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PMID:Similarity between physicochemical properties of recombinant rat prorenin and native inactive renin. 203 49

We have studied the effects of bilateral nephrectomy and adrenalectomy on angiotensinogen concentration, plasma renin activity, and total plasma renin activity obtained after trypsin activation in rats and compared with controls. Our results show that the plasma angiotensinogen concentration of nephrectomized (NX) rats is 5-fold higher than that of adrenalectomized (AX) rats. On the other hand, plasma angiotensinogen concentration of AX rats was about 2.5-fold lower than that of control rats. While NX rat plasma possess no renin activity, its mixing (1:1, v/v) with AX plasma results in 2-fold increase in renin activity over that observed for AX plasma alone. These results suggest that the apparent increase in renin activity upon mixing these two plasmas is at least partly due to an overall increase in angiotensinogen concentration in the mixture. To show that it is not due to activation of NX plasma prorenin by a convertase from AX plasma, prorenin-free NX rat plasma was prepared by using an anti-renin immunoaffinity column. When this prorenin-free NX plasma was mixed (1:1, v/v) with AX, again a 2-fold increase in renin activity was observed which is attributed to the overall increase in plasma angiotensinogen in the mixture. It is concluded that rat plasma prorenin is probably not activated within the circulation by a prorenin convertase from the rat kidney.
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PMID:Effect of angiotensinogen concentration on renin activity following nephrectomy and adrenalectomy: implications in the activation of plasma prorenin. 208 76

A newly synthesized orally active renin inhibitor, N-morpholinoacetyl-(1-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-n-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat. ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n = 6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.
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PMID:ES-8891, an orally active inhibitor of human renin. 211 12


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