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Analogs of 1α,25-dihydroxyvitamin D3 as novel inhibitors of renin biosynthesis
- Source :
-
Journal of Steroid Biochemistry & Molecular Biology . Jun2005, Vol. 96 Issue 1, p59-66. 8p. - Publication Year :
- 2005
-
Abstract
- Abstract: The renin-angiotensin system (RAS) plays a central role in the pathogenesis of hypertension. Recently, we discovered that 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] 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)2D3 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)2D3 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. [Copyright &y& Elsevier]
- Subjects :
- *STEROID hormones
*VITAMIN D
*BIOCHEMICAL engineering
*BLOOD circulation disorders
Subjects
Details
- Language :
- English
- ISSN :
- 09600760
- Volume :
- 96
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Journal of Steroid Biochemistry & Molecular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 18231041
- Full Text :
- https://doi.org/10.1016/j.jsbmb.2005.02.008