Regulation of renal sodium-dependent phosphate co-transporter genes (Npt2a and Npt2c) by all-trans-retinoic acid and its receptors

摘要

pThe type II sodium-dependent phosphate co-transporters Npt2a and Npt2c play critical roles in the reabsorption of Psubi/sub by renal proximal tubular cells. The vitamin A metabolite ATRA (all-itrans/i-retinoic acid) is important for development, cell proliferation and differentiation, and bone formation. It has been reported that ATRA increases the rate of Psubi/sub 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 Psubi/sub homoeostasis and the expression of iNpt2a/i and iNpt2c/i genes in rat kidney. There was no change in the plasma levels of Psubi/sub, but VAD rats significantly increased renal Psubi/sub excretion. Renal brush-border membrane Psubi/sub 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 iNpt2a/i and iNpt2c/i genes was increased markedly by ATRA and a RAR (retinoic acid receptor)-specific analogue TTNPB {4-[iE/i-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 iNpt2c/i gene and were functionally important motifs for transcriptional regulation of human iNpt2c/i by ATRA and 1,25(OH)sub2/subDsub3/sub (1α,25-dihydroxyvitamin Dsub3/sub), in both independent or additive actions. In summary, we conclude that VAD induces hyperphosphaturia through the down-regulation of iNpt2a/i and iNpt2c/i gene expression in the kidney./p