Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice

Dimitra Gkika, Yu Juei Hsu, Annemiete W. Van Der Kemp, Sylvia Christakos, René J. Bindels, Joost G. Hoenderop

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The epithelial Ca2+ channel TRPV5 facilitates apical Ca 2+ 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-D28K. Subsequently, Ca2+ that is bound to calbindin-D28K 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-D28K (TRPV5 -/-, calbindin-D28K-/-, and TRPV5 -/-/calbindin-D28K-/-) 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 Ca 2+ balance. Urine analysis indicated that TRPV5-/-/ calbindin-D28K-/- mice exhibit on both diets hypercalciuria compared with wild-type mice. Ca2+ excretion in TRPV5-/-/calbindin-D28K-/- mice was not significantly different from TRPV5-/- mice, whereas calbindin-D 28K-/- mice did not show hypercalciuria. The similarity between TRPV5-/-/calbindin-D28K-/- and TRPV5-/- mice was supported further by an equivalent increase in renal calbindin-D9K expression and in intestinal Ca2+ hyperabsorption as a result of upregulation of calbindin-D9K 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-D9K and TRPV6, as well as serum parameters of the calbindin-D28K-/- 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-D28K, which possibly is compensated by calbindin-D 9K.

Original languageEnglish (US)
Pages (from-to)3020-3027
Number of pages8
JournalJournal of the American Society of Nephrology
Volume17
Issue number11
DOIs
StatePublished - Nov 2006

All Science Journal Classification (ASJC) codes

  • Nephrology

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