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Critical Role of the Epithelial Ca²⁺ Channel TRPV5 in Active Ca²⁺ Reabsorption as Revealed by TRPV5/Calbindin-D_28K Knockout Mice

Dimitra Gkika^*, Yu-Juei Hsu^*,, Annemiete W. van der Kemp^*, Sylvia Christakos, René J. Bindels^* and Joost G. Hoenderop^*

^* Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan; and Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry, New Jersey Medical School, Newark, New Jersey

Address correspondence to: Dr. Joost G. Hoenderop, 286 Cell Physiology, Radboud University Nijmegen Medical Centre, PO 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 29, 2006. Accepted for publication August 8, 2006.

The epithelial Ca²⁺ channel TRPV5 facilitates apical Ca²⁺ entry during active Ca²⁺ reabsorption in the distal convoluted tubule. In this process, cytosolic Ca²⁺ remains at low nontoxic concentrations because the Ca²⁺ influx is buffered rapidly by calbindin-D_28K. Subsequently, Ca²⁺ that is bound to calbindin-D_28K is shuttled toward the basolateral Ca²⁺ extrusion systems. For addressing the in vivo role of TRPV5 and calbindin-D_28K in the maintenance of the Ca²⁺ balance, single- and double-knockout mice of TRPV5 and calbindin-D_28K (TRPV5^–/–, calbindin-D_28K^–/–, and TRPV5^–/–/calbindin-D_28K^–/–) were characterized. These mice strains were fed two Ca²⁺ diets (0.02 and 2% wt/wt) to investigate the influence of dietary Ca²⁺ content on the Ca²⁺ balance. Urine analysis indicated that TRPV5^–/–/calbindin-D_28K^–/– mice exhibit on both diets hypercalciuria compared with wild-type mice. Ca²⁺ excretion in TRPV5^–/–/calbindin-D_28K^–/– mice was not significantly different from TRPV5^–/– mice, whereas calbindin-D_28K^–/– mice did not show hypercalciuria. The similarity between TRPV5^–/–/calbindin-D_28K^–/– and TRPV5^–/– mice was supported further by an equivalent increase in renal calbindin-D_9K expression and in intestinal Ca²⁺ hyperabsorption as a result of upregulation of calbindin-D_9K and TRPV6 expression in the duodenum. Elevated serum parathyroid hormone and 1,25-dihydroxyvitamin D₃ levels accompanied the enhanced expression of the Ca²⁺ transporters. Intestinal Ca²⁺ absorption and expression of calbindin-D_9K and TRPV6, as well as serum parameters of the calbindin-D_28K^–/– mice, did not differ from those of wild-type mice. These results underline the gatekeeper function of TRPV5 being the rate-limiting step in active Ca²⁺ reabsorption, unlike calbindin-D_28K, which possibly is compensated by calbindin-D_9K.

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