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 (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.
Taketani
Y
Y
Department of Clinical Nutrition, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan.
Segawa
H
H
Chikamori
M
M
Morita
K
K
Tanaka
K
K
Kido
S
S
Yamamoto
H
H
Iemori
Y
Y
Tatsumi
S
S
Tsugawa
N
N
Okano
T
T
Kobayashi
T
T
Miyamoto
K
K
Takeda
E
E
D000818:Animals; D019556:COS Cells; D002117:Calcitriol / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000502:physiology*; D008297:Male; D008871:Microvilli / Q000187:drug effects*; D009687:Nuclear Proteins / Q000032:analysis; D028044:Phosphate-Binding Proteins; D010710:Phosphates / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000503:physiopathology
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D010710:Phosphates; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002117:Calcitriol