Analogs of 1alpha,25-dihydroxyvitamin D(3) as novel inhibitors of renin biosynthesis.
The renin-angiotensin system (RAS) plays a central role in the pathogenesis of hypertension. Recently, we discovered that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] functions as a negative endocrine regulator of renin biosynthesis, which provides a molecular basis to explore the potential of Vitamin D analogs as renin inhibitors to control the RAS. To search for renin-inhibiting Vitamin D analogs, we screened 20 Vitamin D analog compounds using As4.1-hVDR cell (a juxtaglomerular cell line) culture by Northern blot and luciferase reporter assays. We found that the Gemini compounds, which have two side-chains at carbon-20 position, were particularly active in suppressing renin expression. Eight Gemini compounds were identified that were equally or 10- to 100-times more potent than 1,25(OH)(2)D(3) in renin inhibition. These Gemini compounds also potently stimulate 25-hydroxyvitamin D 24-hydroxylase expression in As4.1-hVDR cells. Administration of compound RO-27-5646 [1,25-dihydroxy-21-(3-methyl-3-hydroxy-butyl)-19-nor-cholecalciferol] in mice caused a marked reduction in renal renin mRNA expression without invoking severe hypercalcemia as seen in 1,25(OH)(2)D(3) treatment. These data establish in principle that Vitamin D analogs can indeed inhibit renin expression in vitro and in vivo, and support the notion that low calcemic Vitamin D analogs can potentially be used as therapeutic agents to control the RAS.
Qiao
Guilin
G
Department of Medicine, University of Chicago, MC 4076, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Kong
Juan
J
Uskokovic
Milan
M
Li
Yan Chun
YC
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007606:Juxtaglomerular Apparatus; D051379:Mice; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D000092502:Renin Inhibitors
D002117:Calcitriol; D004791:Enzyme Inhibitors; D012083:Renin; D000092502:Renin Inhibitors