Vitamin D 3 suppresses Npt2c abundance and differentially modulates phosphate and calcium homeostasis in Npt2a knockout mice.

Vitamin D 3 is clinically used for the treatment of vitamin D 3 deficiency or osteoporosis, partially because of its role in regulating phosphate (P i ) and calcium (Ca 2+ ) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in P i homeostasis; however, the role of vitamin D 3 in hypophosphatemia has never been investigated. We administered vehicle or vitamin D 3 to wild-type (WT) mice or hypophosphatemic Npt2a -/- mice. In contrast to WT mice, vitamin D 3 treatment increased plasma P i levels in Npt2a -/- mice, despite similar levels of reduced parathyroid hormone and increased fibroblast growth factor 23. Plasma Ca 2+ was increased ~ twofold in both genotypes. Whereas WT mice were able to increase urinary P i and Ca 2+ /creatinine ratios, in Npt2a -/- mice, P i /creatinine was unchanged and Ca 2+ /creatinine drastically decreased, coinciding with the highest kidney Ca 2+ content, highest plasma creatinine, and greatest amount of nephrocalcinosis. In Npt2a -/- mice, vitamin D 3 treatment completely diminished Npt2c abundance, so that mice resembled Npt2a/c double knockout mice. Abundance of intestinal Npt2b and claudin-3 (tight junctions protein) were reduced in Npt2a -/- only, the latter might facilitate the increase in plasma P i in Npt2a -/- mice. Npt2a might function as regulator between renal Ca 2+ excretion and reabsorption in response to vitamin D 3 .