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 1α-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)2D3) 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)2D3 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)2D3-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)2D3 on the cardiovascular system and kidney.