Hypervitaminosis D Mediates Compensatory Ca2+ Hyperabsorption in TRPV5 Knockout Mice

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Abstract
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-D9K 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-D3-1α-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-D28K (7 ± 2%), calbindin-D9K (32 ± 4%), Na+/Ca2+ exchanger (12 ± 2%), and intestinal TRPV6 (40 ± 8%) and calbindin-D9K (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 1α-OHase knockout mice. It is interesting that a renal Ca2+ leak, as demonstrated in TRPV5−/− mice, persisted in TRPV5−/−/1α-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−/− mice.

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