Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acid-pretreated normal human plasma generates renin activity at 0 degree C and neutral pH by the activation of prorenin. The activation is caused by kallikrein generated from prekallikrein by activated factor XII. Nonacidified plasma also generates renin at 0 degree C, but at a lower rate (cold-promoted activation). In normal plasma, 14% +/- 1% of prorenin (mean +/- SEM, n = 30) was activated during incubation at 0 degree C for 7 days (range 6% to 26%). Cold-promoted activation of prorenin was within the normal range in plasma deficient in factor XI, X, IX, VIIIC, VII, V, prothrombin, or high mol wt kininogen. Cold-promoted activation of prorenin was less than or equal to 1% in plasma deficient in factor XII or prekallikrein. Reconstitution of these plasmas with highly purified factor XII or prekallikrein restored normal prorenin activation. Correction of high mol wt kininogen deficiency had no effect. Thus cold-promoted activation of prorenin depends on the presence of factor XII and prekallikrein, whereas the other clotting factors are not essential. The influence of the inhibitors C1 esterase-inhibitor, alpha 2-macroglobulin, antithrombin III, and alpha 1-antitrypsin on the activation of prorenin was studied in factor XII-deficient plasma from which one or more of these inhibitors had been selectively removed by immunoadsorption. Factor XII was subsequently added, and the generation of renin at 37 degrees C was observed after complete factor XII-high mol wt kininogen-mediated activation of prekallikrein induced by dextran sulfate. No activation of prorenin was observed at 37 degrees C after depletion of C1 esterase inhibitor, alpha 2-macroglobulin, antithrombin III, or alpha 1-antitrypsin. When prekallikrein was activated in plasma depleted of both C1 esterase-inhibitor and alpha 2-macroglobulin, 6% of prorenin was activated in 2 hours at 37 degrees C. After additional depletion of antithrombin III, the activation increased to 47%. These results indicate that the contact activation system is capable of activating prorenin in plasma at physiologic pH and temperature when the three most important kallikrein inhibitors, C1 esterase-inhibitor, alpha 2-macroglobulin, and antithrombin III, are absent.
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PMID:Prorenin-renin conversion by the contact activation system in human plasma: role of plasma protease inhibitors. 636 96

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

It has been suggested that a Factor XII-plasma Prekallikrein dependent pathway might play an important role in the activation of inactive renin. Since Captopril has the potential to affect the kinin-kallikrein system, we have studied in a group of 16 patients with essential hypertension its acute effect both on the levels of active, inactive and total renin, and on the contact phase of the coagulation system. Our results show that a single dose of Captopril (25 mg) induces a rapid and persistent increase of active and total renin, while inactive renin tends to decrease. Together with blood pressure, plasma Prekallikrein(PK), Factor XII(FXII) and Factor XI(FXI) concomitantly decrease, although not significantly, and their values seem to return to basal levels soonafter. However, no correlation was found at any time between the levels of any of these coagulation factors, including PK, and those of inactive, active or the ratio inactive/total renin. In spite of that, it is still possible that an activation of PK, which is likely to occur under Captopril administration, may affect at least the conversion of vessel-bound prorenin rather than the circulating form.
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PMID:Effect of captopril on inactive renin and contact phase of coagulation system. 675 6

Understanding the importance and physiologic activity of the plasma kallikrein/kinin system (KKS) has been thwarted by the absence of an inclusive theory for its assembly and activation. The contact activation hypothesis describes the assembly and activation of this system in test tubes and disease states, but not under physiologic circumstances. Recent investigations have indicated a new cohesive hypothesis for understanding physiologic activation of this system. Prekallikrein (PK) and factor XI (FXI) through high molecular weight kininogen (HK) assemble on a co-localized, multiprotein receptor complex on endothelial cells that consists of at least cytokeratin 1 (CKI), gClqR, and urokinase plasminogen activator receptor (muPAR). When assembled on these proteins, prekallikrein becomes activated to kallikrein by the membrane-expressed enzyme prolylcarboxypeptidase (PRCP). Formed kallikrein then activates factor XII (FXII) for amplification of its activation and single chain urokinase. The plasma kallikrein/kinin system may serve as a physiologic counterbalance to the plasma renin angiotensin system (RAS) by lowering blood pressure and preventing thrombosis. Insights into the integrated role of these two systems may afford the development of novel therapeutic drugs to manage hypertension and thrombosis.
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PMID:Assembly and activation of the plasma kallikrein/kinin system: a new interpretation. 1248 98

Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R(-/-)) have increased thrombosis risk. Paradoxically, the BKB2R(-/-) mice have long bleeding times and delayed carotid artery thrombosis, 78 +/- 6.7 minutes, versus 31 +/- 2.7 minutes in controls. The mechanism(s) for thrombosis protection was sought. In BKB2R(-/-) plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R(-/-) mice have elevated BK 1-5 (160 +/- 75 fmol/mL, vs 44 +/- 29 fmol/mL in controls) and angiotensin II (182 +/- 41 pg/mL, vs 49 +/- 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R(-/-) mice have elevated plasma 6-keto-PGF1alpha (666 +/- 232 ng/mL, vs 23 +/- 5.3 ng/mL in controls) and serum nitrate (61 +/- 5.3 microM, vs 24 +/- 1.8 microM in controls). Treatment with L-NAME (NG-mono-methyl-L-arginine ester) or nimesulide shortens the thrombosis time. BKB2R(-/-) mice have increased angiotensin receptor 2 (AT2R) mRNA and protein expression. Treatment with an AT2R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1alpha. The long bleeding times in BKB2R(-/-) mice also correct with L-NAME and nimesulide therapy. In BKB2R(-/-) mice, angiotensin II binding to an overexpressed AT2R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems.
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PMID:Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin. 1651 58

Venous thromboembolism (VTE) is a multifactorial disease, caused by interacting environmental and genetic risk factors. Gene-centric genotyping strategy is one of the approaches to explore unexplained associations between risk factors and VTE. It was the objective of this study to evaluate, using a gene-centric genotyping strategy, polymorphisms in genes involved in the following pathways: coagulation cascade process, renin-angiotensin or adrenergic systems, lipid metabolism, platelet aggregation. Allele frequency was compared between 677 cases with idiopathic VTE and their matched controls. After Bonferroni adjustment, four single nucleotide polymorphisms (SNPs) were significantly associated with VTE: Factor XI rs925451 polymorphism, factor XI rs2289252 polymorphism, factor II rs1799963 (G20210A) polymorphism and factor V Leiden rs6025. An additive mode of inheritance fitted best both factor XI polymorphisms. In this hospital-based case-control study, two polymorphisms located on the factor XI gene were significantly associated with VTE. Other newly investigated polymorphisms with potentially false negatives may warrant further analyses.
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PMID:Association of common genetic variations and idiopathic venous thromboembolism. Results from EDITh, a hospital-based case-control study. 2035 52

The risk of thrombosis, a globally growing challenge and a major cause of death, is influenced by various factors in the intravascular coagulation, vessel wall, and cellular systems. Among the contributors to thrombosis, the contact activation system and the kallikrein/kinin system, two overlapping plasma proteolytic systems that are often considered as synonymous, regulate thrombosis from different aspects. On one hand, components of the contact activation system such as factor XII initiates activation of the coagulation proteins promoting thrombus formation on artificial surfaces through factor XI- and possibly prekallikrein-mediated intrinsic coagulation. On the other hand, physiological activation of plasma prekallikrein in the kallikrein/kinin system on endothelial cells liberates bradykinin from associated high-molecular-weight kininogen to stimulate the constitutive bradykinin B2 receptor to generate nitric oxide and prostacyclin to induce vasodilation and counterbalance angiotensin II signaling from the renin-angiotensin system which stimulates vasoconstriction. In addition to vascular tone regulation, this interaction between the kallikrein/kinin and renin-angiotensin systems has a thrombo-regulatory role independent of the contact pathway. At the level of the G-protein coupled receptors of these systems, defective bradykinin signaling due to attenuated bradykinin formation and/or decreased B2 receptor expression, as seen in murine prekallikrein and B2 receptor null mice, respectively, leads to compensatory overexpressed Mas, the receptor for angiotensin-(1-7) of the renin-angiotensin system. Mas stimulation and/or its increased expression contributes to maintaining a healthy vascular homeostasis by generating graded elevation of plasma prostacyclin which reduces thrombosis through two independent pathways: (1) increasing the vasoprotective transcription factor Sirtuin 1 to suppress tissue factor expression, and (2) inhibiting platelet activation. This review will summarize the recent advances in this field that support these understandings. Appreciating these subtle mechanisms help to develop novel anti-thrombotic strategies by targeting the vascular receptors in the renin-angiotensin and the kallikrein/kinin systems to maintain healthy vascular homeostasis.
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PMID:Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems. 3271 19