Vitamin D activates type A natriuretic peptide receptor gene transcription in inner medullary collecting duct cells.
Many clinical and animal studies suggest that vitamin D and its metabolites have beneficial effects in the cardiovascular and renal systems. Using immunologic and enzymatic assays, vitamin D receptor and 25 hydroxyvitamin D3 1alpha-hydroxylase activity were found in inner medullary collecting duct (IMCD) cells suggesting an autocrine/paracrine role in this nephron segment. In this study, we examined the ability of 1,25 dihydroxyvitamin D3 (1,25(OH)(2)D3) to regulate the expression of the vasculoprotective natriuretic peptide receptor-A gene in these cells in culture. Treatment of the cells with 1,25(OH)(2)D3 caused a doubling of natriuretic peptide-dependent cyclic guanosine monophosphate production and a significant increase in natriuretic peptide receptor-A protein expression. This was accompanied by significant increases in receptor mRNA levels and gene-promoter activity. Mutation of a vitamin D response element, positioned upstream from the gene start site, resulted in a complete loss of 1,25(OH)(2)D3-dependent induction but not the induction by hypertonic stimuli. Introduction of small interfering RNA directed against the vitamin D receptor into the IMCD cells resulted in decreased natriuretic peptide receptor-A gene promoter activity and protein. The increase in this receptor expression may account for some of the reported beneficial effect of 1,25(OH)(2)D3 on the cardiovascular system and kidney.
Chen
S
S
Diabetes Center, University of California at San Francisco, San Francisco, California 94143-0540, USA. schen@diabetes.ucsf.edu
Olsen
K
K
Grigsby
C
C
Gardner
D G
DG
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology; D002117:Calcitriol / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002320:Cardiovascular Physiological Phenomena; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014807:Vitamin D / Q000502:physiology*
D002120:Calcium Channel Agonists; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014807:Vitamin D; D009320:Atrial Natriuretic Factor; D012964:Sodium; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D002117:Calcitriol; D006152:Cyclic GMP