Vitamin D₃ suppresses Npt2c abundance and differentially modulates phosphate and calcium homeostasis in Npt2a...

Vitamin D₃ is clinically used for the treatment of vitamin D₃ deficiency or osteoporosis, partially because of its role in regulating phosphate (P_i) and calcium (Ca²⁺) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in P_i homeostasis; however, the role of vitamin D₃ in hypophosphatemia has never been investigated. We administered vehicle or vitamin D₃ to wild-type (WT) mice or hypophosphatemic Npt2a^-/- mice. In contrast to WT mice, vitamin D₃ treatment increased plasma P_i levels in Npt2a^-/- mice, despite similar levels of reduced parathyroid hormone and increased fibroblast growth factor 23. Plasma Ca²⁺ was increased ~ twofold in both genotypes. Whereas WT mice were able to increase urinary P_i and Ca²⁺/creatinine ratios, in Npt2a^-/- mice, P_i/creatinine was unchanged and Ca²⁺/creatinine drastically decreased, coinciding with the highest kidney Ca²⁺ content, highest plasma creatinine, and greatest amount of nephrocalcinosis. In Npt2a^-/- mice, vitamin D₃ 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 Ca²⁺ excretion and reabsorption in response to vitamin D₃.