Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5
Joost G.J. Hoenderop, … , Edith Hummler, René J.M. Bindels
Joost G.J. Hoenderop, … , Edith Hummler, René J.M. Bindels
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1906-1914. https://doi.org/10.1172/JCI19826.
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Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Abstract

Ca2+ ions play a fundamental role in many cellular processes, and the extracellular concentration of Ca2+ is kept under strict control to allow the proper physiological functions to take place. The kidney, small intestine, and bone determine the Ca2+ flux to the extracellular Ca2+ pool in a concerted fashion. Transient receptor potential (TRP) cation channel subfamily V, members 5 and 6 (TRPV5 and TRPV6) have recently been postulated to be the molecular gatekeepers facilitating Ca2+ influx in these tissues and are members of the TRP family, which mediates diverse biological effects ranging from pain perception to male aggression. Genetic ablation of TRPV5 in the mouse allowed us to investigate the function of this novel Ca2+ channel in maintaining the Ca2+ balance. Here, we demonstrate that mice lacking TRPV5 display diminished active Ca2+ reabsorption despite enhanced vitamin D levels, causing severe hypercalciuria. In vivo micropuncture experiments demonstrated that Ca2+ reabsorption was malfunctioning within the early part of the distal convolution, exactly where TRPV5 is localized. In addition, compensatory hyperabsorption of dietary Ca2+ was measured in TRPV5 knockout mice. Furthermore, the knockout mice exhibited significant disturbances in bone structure, including reduced trabecular and cortical bone thickness. These data demonstrate the key function of TRPV5 in active Ca2+ reabsorption and its essential role in the Ca2+ homeostasis.

Authors

Joost G.J. Hoenderop, Johannes P.T.M. van Leeuwen, Bram C.J. van der Eerden, Ferry F.J. Kersten, Annemiete W.C.M. van derKemp, Anne-Marie Mérillat, Jan H. Waarsing, Bernard C. Rossier, Volker Vallon, Edith Hummler, René J.M. Bindels

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Figure 1

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Creation of null mutant mice for the TRPV5 gene locus. (a) Targeted inac...
Creation of null mutant mice for the TRPV5 gene locus. (a) Targeted inactivation of the TRPV5 gene. Top, exon 13, encoding the pore-forming unit of TRPV5, is flanked by loxP sites. Middle, recombined TRPV5loxneo locus. Bottom, targeted allele in which exon 13 is deleted by Cre recombinase. Black boxes indicate exons; probe and genotype primers (A–D) are depicted. neoR, neomycin resistance cassette. (b) Representative Southern blot analysis of BamHI-digested tail-derived DNA isolated from TRPV5+/+, TRPV5+/–, and TRPV5–/– mice. (c) Identification of mouse genotype by PCR analysis of tail-derived DNA. The PCR product in the upper gel shows the presence of the wild-type allele (+/+) using primers C and D; the lower gel shows the knockout allele (–/–) using primers A and B. Both alleles are detected in heterozygous animals (+/–). (d) TRPV5 (top images) and kallikrein (lower images) immunohistochemical costaining of kidney cortex from TRPV5+/+ and TRPV5–/– mice. (e) Immunopositive TRPV6 staining of renal distal tubules from TRPV5+/+ and TRPV5–/– mice. A color version of this figure is available online as Supplementary Figure 1 (http://www.jci.org/cgi/content/full/112/12/1906/DC1).