Hypervitaminosis D mediates compensatory Ca²⁺ hyperabsorption in TRPV5 knockout mice

Vitamin D plays an important role in Ca²⁺ homeostasis by controlling Ca²⁺ (re)absorption in intestine, kidney, and bone. The epithelial Ca²⁺ channel TRPV5 mediates the Ca²⁺ entry step in active Ca²⁺ reabsorption. TRPV5 knockout (TRPV5^-/-) mice show impaired Ca²⁺ reabsorption, hypercalciuria, hypervitaminosis D, and intestinal hyperabsorption of Ca²⁺. Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D _9K expression compared with wild-type mice. For addressing the role of the observed hypervitaminosis D in the maintenance of Ca²⁺ homeostasis and the regulation of expression levels of the Ca²⁺ transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D ₃-la-hydroxylase double knockout (TRPV5^-/-/1α- OHase^-/-) mice, which show undetectable serum 1,25(OH) ₂D₃ levels, were generated. TRPV5^-/-/1α- OHase^-/- mice displayed a significant hypocalcemia compared with wild-type mice (1.10 ± 0.02 and 2.54 ± 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D_28K (7 ± 2%), calbindin-D_9K (32 ± 4%), Na⁺/Ca²⁺ exchanger (12 ± 2%), and intestinal TRPV6 (40 ± 8%) and calbindin-D_9K (26 ± 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5^-/-/1α-OHase^-/- mice, more pronounced than observed in single TRPV5 or OHase knockout mice. It is interesting that a renal Ca²⁺ leak, as demonstrated in TRPV5^-/- mice, persisted in TRPV5^-/-/α-OHase^-/- mice, but a compensatory upregulation of intestinal Ca²⁺ transporters was abolished. In conclusion, the elevation of serum 1,25(OH)₂D₃ levels in TRPV5^-/- mice is responsible for the upregulation of intestinal Ca²⁺ transporters and Ca²⁺ hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca²⁺ reabsorption in TRPV5^-7- mice.