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

• Published in: The Journal of biological chemistry 1998-06, Vol.273 (23), p.14575-14581
• Main Authors: Taketani, Y, Segawa, H, Chikamori, M, Morita, K, Tanaka, K, Kido, S, Yamamoto, H, Iemori, Y, Tatsumi, S, Tsugawa, N, Okano, T, Kobayashi, T, Miyamoto, K, Takeda, E
• Format: Article
• Language: English
• Subjects: Animals; Calcitriol - pharmacology; Carrier Proteins - metabolism; COS Cells; DNA-Binding Proteins - analysis; Gene Expression Regulation - genetics; Humans; Immunohistochemistry; Kidney Cortex - physiology; Male; Microvilli - drug effects; Nuclear Proteins - analysis; Phosphate-Binding Proteins; Phosphates - metabolism; Promoter Regions, Genetic - genetics; Rats; Rats, Wistar; Receptors, Calcitriol - metabolism; Receptors, Retinoic Acid - metabolism; Retinoid X Receptors; RNA, Messenger - metabolism; Transcription Factors - metabolism; Vitamin D Deficiency - physiopathology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.273.23.14575

Vitamin D is an important regulator of phosphate homeostasis. The effects of vitamin D on the expression of renal Na+-dependent inorganic phosphate (Pi) transporters (types I and II) were investigated. In vitamin D-deficient rats, the amounts of type II Na+-dependent Pi 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 D3 (1,25-(OH)2D3) to vitamin D-deficient rats increased the initial rate of Pi 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 Pi transporter NaPi-3 gene was increased markedly by 1,25-(OH)2D3 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 Pi homeostasis is through the modulation of the expression of type II Na+-dependent Pi transporter genes in the juxtamedullary kidney cortex.