Regulation of renal sodium-dependent phosphate co-transporter genes (Npt2a and Npt2c) by all-trans-retinoic acid and its receptors.
The type II sodium-dependent phosphate co-transporters Npt2a and Npt2c play critical roles in the reabsorption of Pi by renal proximal tubular cells. The vitamin A metabolite ATRA (all-trans-retinoic acid) is important for development, cell proliferation and differentiation, and bone formation. It has been reported that ATRA increases the rate of Pi transport in renal proximal tubular cells. However, the molecular mechanism is still unknown. In the present study, we observed the effects of a VAD (vitamin A-deficient) diet on Pi homoeostasis and the expression of Npt2a and Npt2c genes in rat kidney. There was no change in the plasma levels of Pi, but VAD rats significantly increased renal Pi excretion. Renal brush-border membrane Pi uptake activity and renal Npt2a and Npt2c expressions were significantly decreased in VAD rats. The transcriptional activity of a luciferase reporter plasmid containing the promoter region of human Npt2a and Npt2c genes was increased markedly by ATRA and a RAR (retinoic acid receptor)-specific analogue TTNPB {4-[E-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphtalenyl)-1-propenyl] benzoic acid} in renal proximal tubular cells overexpressing RARs and RXRs (retinoid X receptors). Furthermore, we identified RAREs (retinoic acid-response elements) in both gene promoters. Interestingly, the half-site sequences (5'-GGTTCA-3': -563 to -558) of 2c-RARE1 overlapped the vitamin D-responsive element in the human Npt2c gene and were functionally important motifs for transcriptional regulation of human Npt2c by ATRA and 1,25(OH)2D3 (1alpha,25-dihydroxyvitamin D3), in both independent or additive actions. In summary, we conclude that VAD induces hyperphosphaturia through the down-regulation of Npt2a and Npt2c gene expression in the kidney.
Masuda
Masashi
M
Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-Cho, Japan.
Yamamoto
Hironori
H
Kozai
Mina
M
Tanaka
Sarasa
S
Ishiguro
Mariko
M
Takei
Yuichiro
Y
Nakahashi
Otoki
O
Ikeda
Shoko
S
Uebanso
Takashi
T
Taketani
Yutaka
Y
Segawa
Hiroko
H
Miyamoto
Ken-ichi
K
Takeda
Eiji
E
D000818:Animals; D015153:Blotting, Western; D004032:Diet; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000502:physiology*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*
D011955:Receptors, Drug; C493556:Slc34a1 protein, rat; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D014212:Tretinoin