Regulation of type II renal Na+-dependent inorganic phosphate transporters by 1,25-dihydroxyvitamin D3 -: Identification of a vitamin D-responsive element in the human NAPI-3 gene

Vitamin D is an important regulator of phosphate homeostasis. The effects of vitamin D on the expression of renal Na+-dependent inorganic phosphate (P-i) transporters (types I and II) were investigated. In vitamin D-deficient rats, the amounts of type II Na+-dependent P-i transporter (NaPi-2) protein and mRNA were decreased in the juxtamedullary kidney cortex, but not in the superficial cortex, compared with control rats. The administration of 1,25-dihydroxyvitamin D-3 (1,25-(OH)(2)D-3) to vitamin D-deficient rats increased the initial rate of P-i uptake as well as the amounts of NaPi-2 mRNA and protein in the juxtamedullary cortex. The transcriptional activity of a luciferase reporter plasmid containing the promoter region of the human type II Na+-dependent P-i transporter NaPi-3 gene was increased markedly by 1,25-(OH)(2)D-3 in COS-7 cells expressing the human vitamin D receptor. A deletion and mutation analysis of the NaPi-3 gene promoter identified the vitamin D-responsive element as the sequence 5'-GGGGCAGCAAGGGCA-3' nucleotides -1977 to -1963 relative to the transcription start site. This element bound a heterodimer of the vitamin D receptor and retinoid X receptor, and it enhanced the basal transcriptional activity of the promoter of the herpes simplex virus thymidine kinase gene in an orientation-independent manner. Thus, one mechanism by which vitamin D regulates P-i homeostasis is through the modulation of the expression of type II Na+-dependent P-i transporter genes in the juxtamedullary kidney cortex.