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

Abstract

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.

Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo

“…These effects were independent of 1,25(OH) 2 D 3 and serum phosphorus. However, a similar study using mice of the same genotype could not confirm these findings (14). The reason(s) underlying the differing results in these two studies is unknown.…”

Sodium-Dependent Phosphate Cotransporters: Lessons from Gene Knockout and Mutation Studies

“…The vitamin D 3 (1,25-Dihydroxyvitamin D 3 ) and dietary Pi depletion are thought to be the most important physiological stimuli of intestinal Pi absorption and they act by increasing the abundance of the NaPi-IIb transporter protein. [53][54][55][56] The intestine absorbs up to 70% of the ingested Pi. Shibasaki et al 57 reported that the full ablation of mouse NaPi-IIb resulted in embryonic lethality.…”

Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b+/−mice

“…The proximal intestine refers to the duodenum and the proximal part of the jejunum. The distal intestine refers to the late jejunum and ileum (16). BBMVs were prepared from intestine using the Ca 2ϩ precipitation method and used for Western blotting analysis as described previously (37,38).…”

“…There were no significant differences between the intestinal BBMVs of Npt2b ϩ/ϩ and Npt2b ϩ/Ϫ mice regardless of whether they were or were not treated with adenine. Uptake of 32 P into BBMVs was measured by the rapid filtration technique as described previously (16,37,38). The P i transport rate into the intestinal BBMV was determined at 60 s and at 60 min (equilibrium value) at 25°C with an inward gradient of 100 mM NaCl 2 or 100 mM KCl and 0.1 mM KH2PO4 (pH 7.5).…”

“…Intestinal absorption of P i is mediated primarily via the type IIb sodiumphosphate transporter Npt2b (29,40,43,44). 1,25-Dihydroxyvitamin D 3 and dietary P i depletion are thought to be the most important physiological stimuli of intestinal P i absorption and act by increasing the abundance of Npt2b protein (11,16,27,42).…”