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

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