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)

Staurosporine (STS) is a very potent broad-range kinase inhibitor, and its antiproliferative properties made it a lead compound for protein kinase C (PKC) inhibitors with therapeutic potential. Because STS also causes hypotension, we investigated in this study whether it directly interferes with the terminal steps of aldosterone biosynthesis; these are catalysed by a mitochondrial steroid hydroxylase system consisting of adrenodoxin reductase, adrenodoxin, and the cytochrome P450 enzyme hCYP11B2 (aldosterone synthase). Here we demonstrate that nanomolar concentrations of STS significantly reduced aldosterone synthase activity in transiently transfected COS-1 cells and in stably transfected V79MZh11B2 cells (IC50 = 11 nM). However, STS did not inhibit bovine aldosterone synthase in a reconstituted steroid hydroxylation assay. In transiently transfected COS-1 cells, the protein level of adrenodoxin (but not that of adrenodoxin reductase or of hCYP11B2) was significantly reduced after treatment with 2 nM STS. Finally, we show that STS treatment (1 microg/day) of mice reduced their aldosterone/renin ratio by almost 50% (p = 0.015). To the best of our knowledge, this is the first report of a direct in vivo effect of STS on the renin-angiotensin-aldosterone system. We conclude (i) that the hypotensive effect of staurosporine is at least partly due to inhibition of aldosterone biosynthesis via adrenodoxin depletion, and (ii) that aldosterone biosynthesis can be regulated in vivo at the level of adrenodoxin availability.
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PMID:Inhibition of aldosterone biosynthesis by staurosporine. 1620 87

Vitamin D3 is modified by vitamin D3 25-hydroxylase in the liver, and by 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) in the kidney, to form the active metabolite 1alpha,25-dihydroxyvitamin D3. Several vitamin D receptor (VDR) activators, including paricalcitol and calcitriol, are currently available for the treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients encounter a much higher risk of cardiovascular disease than do members of the general public, and recent clinical observations have shown that VDR activator therapy provides survival benefit for CKD patients in the rank order of paricalcitol > calcitriol > no VDR activator therapy, independent of parathyroid hormone, phosphorus and calcium. One possible explanation for this observation is that VDR activators exert a positive impact on cardiovascular functions. Studies in animals with disrupted genes involved in the vitamin D signaling pathway have provided some interesting data. For example, in mice lacking VDR or CYP27B1, it was found that in addition to the expected phenotype (hypocalcemia, secondary hyperparathyroidism and osteomalacia), expression of renin or atrial natriuretic peptide was elevated. The mice also developed hypertension and cardiac hypertrophy. Gene expression profiling studies have revealed that VDR may play a role in regulating smooth-muscle-cell (SMC) proliferation, thrombosis, fibrinolysis and vessel relaxation. Paricalcitol and calcitriol are equally potent at suppressing plasminogen activator inhibitor-1 synthesis and inhibiting cellular proliferation in human coronary artery SMCs. The effect of VDR activators on the modulation of renin expression and vascular functions may be factors that contribute to reduced mortality and morbidity risk in VDR-activator-treated CKD patients. In this review, we discuss recent preclinical and clinical data regarding the role of VDR and its ligands in the cardiovascular system.
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PMID:Cardiovascular disease in chronic kidney failure: the role of VDR activators. 1655 80