Hypophosphatemia in vitamin D receptor null mice: effect of rescue diet on the developmental changes in renal Na+ -dependent phosphate cotransporters.

We analyzed vitamin D receptor (VDR) (-/-) mice fed either a normal diet or a rescue diet. Weanling VDR (-/-) mice had hypophosphatemia and hyperphosphaturia. Renal Na(+)-dependent inorganic phosphate (Pi) cotransport activity was significantly decreased in weanling VDR (-/-) mice. In VDR (+/+) mice, renal Npt2a/Npt2c/PiT-2 protein levels were significantly increased at 21 and 28 days of age compared with that at 1 day of age. Npt2c and PiT-2 protein levels were maximally expressed at 28 days of age. Npt2a protein levels were significantly decreased in mice at 28 days of age compared with 21 and 60 days of age. In VDR (-/-) mice, Npt2a/Npt2c/PiT-2 protein levels were considerably lower than those in age-matched VDR (+/+) mice at 21 and 28 days of age. The reduced Npt2a/Npt2c/PiT-2 protein recovered completely in VDR-null mice fed the rescue diet. Although Pi transport activity and Npt2b were reduced in the proximal intestine in VDR (-/-) mice, Npt2b protein levels were not reduced in the distal intestine in VDR (-/-) mice. The rescue diet did not affect intestinal Npt2b protein levels in VDR (-/-) mice. Thus, reduced intestinal Pi absorption in VDR (-/-) mice does not seem to be the only factor that causes hypophosphatemia; reduced Npt2a, Npt2c, or PiT-2 protein levels during development might also cause hypophosphatemia and rickets in VDR (-/-) mice. Furthermore, dietary intervention completely normalized the expression of the renal phosphate transporters (Npt2a/Npt2c/PiT-2) in VDR (-/-) mice, suggesting that the lack of VDR activity is not the cause of impaired renal phosphate reabsorption.