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)

Plasma prorenin is an inactive form of renin (EC 3.4.99.19) that can be converted to active renin in acid-treated plasma by an endogenous serine protease that is active at alkaline pH (alkaline phase activation). To identify this enzyme we first tested the ability of Hageman factor fragments, plasma kallikrein (EC 3.4.21.8), and plasmin (EC 3.4.21.7) to activate prorenin in acid-treated plasma. All three enzymes initiated prorenin activation; 50% activation was achieved with Hageman factor fragments at 1 microgram/ml, plasma kallikrein at 2-4 microgram/ml, or plasmin at 5-10 microgram/ml. We then showed that the alkaline phase of acid activation occurred normally in plasminogen-free plasma but was almost completely absent in plasmas deficient in either Hageman factor or prekallikrein; alkaline phase activation was restored to these latter plasmas when equal parts were mixed together. Therefore, both Hageman factor and prekallikrein were required for alkaline phase activation to occur. We then found that, although plasma kallikrein could activate prorenin in plasma deficient in either Hageman factor or prekallikrein, Hageman factor fragments were unable to activate prorenin in prekallikrein-deficient plasma. These studies demonstrate that alkaline phase prorenin activation is initiated by Hageman factor-dependent conversion of prekallikrein to kallikrein which, in turn, leads to activation of prorenin. In this fashion, we have revealed a possible link between the coagulation-kinin pathway and the renin-angiotensin system.
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PMID:Initiation of plasma prorenin activation by Hageman factor-dependent conversion of plasma prekallikrein to kallikrein. 4 5

1. Plasma prorenin is an inactive form of renin that is converted into active renin at alkaline pH in previously acidified plasma; this conversion of prorenin into renin is mediated by Hageman factor-dependent activation of prekallikrein, which, in turn, leads to prorenin activation. 2. Since plasma kallikrein can activate plasminogen, the present studies were designed to evaluate whether alkaline-phase activation of prorenin by plasma kallikrein is mediated via plasminogen activation. 3. We demonstrated that plaminogen is present in acid-treated plasma in sufficient quantity to convert prorenin into renin after activation by streptokinase. 4. However, alkaline-phase activation was completely normal in plasminogen-free plasma. 5. Therefore alkaline-phase activation of plasma prorenin is mediated by plasma kallikrein but is not dependent on kallikrein activation of plasminogen.
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PMID:Plasmin can activate plasma prorenin but is not required for the alkaline phase of acid activation. 4 36

Plasma concentrations of various physiologically important proteins, including transferrin, ceruloplasmin, haptoglobin, transcortin, sex hormone-binding globulin, thyroxin-binding globulin, renin-substrate, fibrinogen, coagulation factors VII and VIII, antithrombin-III, plasminogen, prealbumin, albumin, retinol-binding protein, and lipoprotein fractions, were measured before treatment with oral contraceptives (OCs) and then again after 6 cycles of treatment to measure changes in the daily synthesis rate of 2 proteins, albumin and fibrinogen, under the influence of various OC formulations. Results are presented for 38 women using high-dose (50 mcg estrogen) preparations, 38 using low-dose (30 mcg estrogen preparations), and 20 using a continuous-dose progestagen-only minipill (30 mcg levonorgestrel). Most of the proteins measured showed significant alterations in women using the high-dose OCs. Changes with the lower dose product were less marked, and most proteins were unchanged in women using the minipill. (For example, synthesis rates of fibrinogen, mg/kg/day, for controls, high-, low-, and mini-dose subjects were: 24, 43, 28, and 25 respectively). Data from isotope studies indicated that synthetic estrogens act on liver synthesis and secretion rates for many plasma proteins; hence the clinical associations seen with OC use.
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PMID:Oral contraceptives and plasma protein metabolism. 22 92

Five women with premature ovarian failure were studied in a randomized cross-over design to compare the biochemical effects of transdermal to oral estradiol administration when used in doses appropriate for endometrial preparation in a donor oocyte program. Patients randomly received increasing dosages of oral micronized or transdermal estradiol for 4 week, with progesterone added in the last 2 weeks, to mimic a normal hormonal cycle. Serum samples were assayed throughout treatment and compared to those from normally cycling premenopausal controls. In general, serum estradiol remained within the normal range in both treatment groups, whereas peak serum estrone levels were 10-fold higher in the orally treated group than those in the transdermally treated group. Serum levels of sex hormone-binding globulin, thyroid binding globulin, and renin substrate were all significantly elevated by day 14 in the orally treated patients and unchanged in the transdermal subjects. While plasminogen was unaltered by either route of administration, antithrombin-III levels fell with both treatments. Changes in gonadotropin levels were similar in both groups, with suppression of FSH by the end of the simulated cycles, but not into the normal premenopausal range. In conclusion, both estrogen replacement regimens provided near-normal serum estradiol profiles. However, despite the relatively high doses necessary to mimic a hormonally normal cycle, the transdermal route did not significantly alter the hepatic parameters studied, suggesting that this route of administration may have less adverse hepatic effects.
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PMID:Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. 190 93

Venous occlusion of the left arm in consenting men was induced for 10 or 20 min to stimulate local fibrinolytic and other proteases, thereby favouring the conversion of prorenin to renin. Using the two techniques cryoactivation and tryptic activation, we found that plasma active renin increased significantly after such occlusion (10 and 20 min) while prorenin rose more convincingly and progressively from 10 to 20 min. The renin increase can be partially attributed to hemoconcentration, but in vivo production and (or) local activation of prorenin to renin cannot be excluded. The prorenin rise can apparently be attributed to local extrarenal production, and not to hemoconcentration or influx, since it was progressive and neither prorenin nor renin levels were raised at all in blood circulating outside the occluded arm. Prekallikrein and plasminogen levels were elevated in occlusion plasmas, but responsibility of these enzyme systems for any enhanced activation of prorenin was not established. The trypsin inhibitory capacity was also elevated, increasing the requirement of trypsin to achieve optimal activation of prorenin, but not changing the prorenin estimate itself. Thus, prorenin appears to be released extrarenally, within the vasculature of an occluded arm, while in vitro evidence suggests that the mechanisms for its activation were stimulated. The importance of such extrarenal production and activation of prorenin for renin production under other physiological or pathophysiological conditions remains to be determined.
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PMID:Extrarenal production and activation of human plasma prorenin: the evidence after venous occlusion. 265 95

The fate of circulating inactive prorenin was examined in patients and volunteers. Prorenin was activated either by acid-dialysis with warming at pH 3.3 or with trypsin. The results were similar but omission of warming reduced the value by 13%. In 6 volunteers, 20 min forearm venous occlusion raised regional total (T) and inactive (I) plasma renin concentration (PRC) by 51% and 48% without change of active (A) renin. During intense forearm exercise the ratio APRC: IPRC did not change in muscle or skin venous blood. Body anaerobic exercise increased APRC 3.7-fold without change in IPRC. These procedures activate plasminogen but are without effect on prorenin. In 18 patient with stable angina, TPRC was lower in coronary sinus than arterial blood (p less than 0.001) but APRC was not affected. A-V differences were not detected across the leg. Prorenin is apparently stable in the circulation but extracted by the heart.
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PMID:Potential functions of plasma prorenin; regional activation and tissue extraction. 330 99

The contact phase of blood coagulation in a group of patients suffering from essential hypertension was studied before and after captopril administration. The baseline levels of factor XII, factor XI and plasminogen were significantly higher than in normals and correlated with baseline diastolic blood pressure levels. On the contrary, plasma prekallikrein was not significantly different from normal. These results suggest the presence of a hypercoagulable state in essential hypertension. After captopril administration, factor XII, factor XI and prekallikrein rapidly decreased, perhaps as a consequence of the drug's effect on the vascular endothelial surface. There was no correlation between the changes of active and inactive renin and the changes of prekallikrein and plasminogen levels. Our data do not support the view that factor XII-plasma kallikrein or plasmin dependent pathways are involved in the activation of inactive renin in vivo. Captopril, by provoking rapid pressure changes, appears to be able to affect the clotting system.
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PMID:The contact phase of blood coagulation and renin activation in essential hypertension before and after captopril. 638 34

Venom of the puff adder (Bitis arietans) contains a potent, basic, Mr 24,000 metalloproteinase activity that can destroy all detectable trypsin and chymotrypsin inhibitory activity, when venom is incubated with human plasma. We have found that during such incubation, concomitant activation of inactive renin occurs. In an examination of the mechanism involved we now report the activation, in addition, of plasma prekallikrein and serine proteinase activity, but not plasminogen, when human plasma is incubated with venom. Furthermore, venom was not able to release active trypsin from its complex with alpha 1-proteinase inhibitor and human renin was not inhibited by alpha 1-proteinase inhibitor. The activities in venom and venom/plasma mixtures were analysed using Sephacryl S-200 gel filtration and the effect of 10 mM EDTA and 5 mM phenylmethanesulphonyl fluoride on activities in column fractions was tested. The inactive-renin-activating, plasma prekallikrein-activating and serine proteinase-activating activities could be accounted for to a large extent by a venom metalloproteinase which was estimated to have a Mr of 24,000 by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis. This enzyme activity appeared to complex with alpha 2-macroglobulin when venom was mixed with plasma. Since both EDTA and phenylmethanesulphonyl fluoride could inhibit the activation of inactive renin by this metalloproteinase, it is suggested that the enzyme activates serine proteinase(s), which then activate inactive renin. Plasma kallikrein may have a role in this process. Additional peaks of inactive-renin-activating activity eluted from Sephacryl S-200 at Mr 30,000 and 80,000 (minor) and an additional, minor peak of caseinolytic activity eluted at Mr 60,000. The Mr 24,000 metalloproteinase in venom may have considerable utility in activating inactive renin at physiological pH owing to its ability to destroy plasma proteinase inhibitors at the same time.
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PMID:Mechanism of activation of inactive renin in human plasma by puff adder venom. 645 70

Plasminogen can be activated by intrinsic activators that circulate in plasma in a precursor form, by extrinsic activator originating from tissues or the vessel wall and by the exogenous activators, urokinase and streptokinase. Tissue activator and vascular activator are probably identical. Dialysis of plasma against pH 4.0 buffer causes denaturation of the plasmin inhibitors, alpha 2-antiplasmin and C1-inhibitor, while alpha 2-macroglobulin is left intact. Incubation of pH 4.0-pretreated plasma with urokinase or streptokinase at pH 7.5 led to activation of plasminogen and prorenin. Incubation of a plasma fraction, which contained plasminogen and prorenin but no alpha 2-antiplasmin and renin, with highly purified tissue plasminogen activator also led to activation of prorenin. The vasopressin analogue, 1-desamino-8-D-arginine vasopressin (DDAVP), is a potent stimulant for the release of extrinsic activator into the bloodstream. After infusion of DDAVP, 0.4 micrograms/kg, into normal subjects, parallel increments in plasma fibrinolytic activity and renin were observed. Infusion of DDAVP into patients with type IV hyperlipoproteinaemia had little effect on plasma fibrinolytic activity and the response of plasma renin was also subnormal. These observations warrant further studies on a possible role for plasminogen activators in prorenin activation in vivo.
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PMID:Activation of plasma prorenin by plasminogen activators in vitro and increase in plasma renin after stimulation of fibrinolytic activity in vivo. 675 94

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


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