1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. cyan@medicine.bsd.uchicago.edu
Yan Chun
YC
Li
Juan
J
Kong
Minjie
M
Wei
Zhou-Feng
ZF
Chen
Shu Q
SQ
Liu
Li-Ping
LP
Cao
D000804:Angiotensin II / Q000097:blood; D000818:Animals; D002117:Calcitriol / Q000096:biosynthesis / Q000494:pharmacology*; D004327:Drinking Behavior / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D006996:Hypocalcemia / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D012982:Sodium, Dietary / Q000008:administration & dosage; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics
D009479:Neuropeptides; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D012982:Sodium, Dietary; D015534:Trans-Activators; D000804:Angiotensin II; D012083:Renin; D002117:Calcitriol