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Hypervitaminosis D Mediates Compensatory Ca²⁺ Hyperabsorption in TRPV5 Knockout Mice

Kirsten Y. Renkema^*, Tom Nijenhuis^*, Bram C.J. van der Eerden, Annemiete W.C.M. van der Kemp^*, Harrie Weinans, Johannes P.T.M. van Leeuwen, René J.M. Bindels^* and Joost G.J. Hoenderop^*

^* Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and Departments of Internal Medicine and Orthopedics, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands

Address correspondence to: Dr. Joost G.J. Hoenderop, Radboud University Nijmegen Medical Centre, 160 Cell Physiology, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands. Phone: +31-24-3610571; Fax: +31-24-3616413; E-mail: j.hoenderop{at}ncmls.ru.nl

Received for publication June 17, 2005. Accepted for publication July 18, 2005.

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-D₃-1-hydroxylase double knockout (TRPV5^–/–/1-OHase^–/–) mice, which show undetectable serum 1,25(OH)₂D₃ levels, were generated. TRPV5^–/–/1-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^–/–/1-OHase^–/– mice, more pronounced than observed in single TRPV5 or 1-OHase knockout mice. It is interesting that a renal Ca²⁺ leak, as demonstrated in TRPV5^–/– mice, persisted in TRPV5^–/–/1-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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