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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Article

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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Renal and duodenal Ca2+ transport assays. (a) Fractional Ca2+ delivery t...
Renal and duodenal Ca2+ transport assays. (a) Fractional Ca2+ delivery to the LPT, to the distal convolution (DC), and to urine (U), measured by micropuncture experiments in TRPV5+/+ and TRPV5–/– mice. (b) Relation between K+ concentration in tubular fluid of the distal convolution and fractional Ca2+ delivery to these sites. Low K+ concentrations indicate early puncture sites and high K+ concentrations late aspects of distal convolution (2). Values are means ± SEM of six mice per group for urine data and of 19–24 nephrons per group for LPT and distal convolution collections. *P < 0.05 versus TRPV5+/+. (c) Changes in serum Ca2+ (ΔμM) within 10 minutes of administration of 45Ca2+ by oral gavage in TRPV5+/+ and TRPV5–/– mice (n = 12). Data are averaged values ± SEM from mice 8 weeks old. *P < 0.05, significant difference from wild-type mice. (d) Expression of calbindin-D28K and NCX1 mRNA in kidney cortexes of TRPV5+/+ and TRPV5–/– mice (n = 9), assessed by quantitative real-time PCR analysis and calculated as a ratio to HPRT RNA. (e) Expression of TRPV6 and calbindin-D9K mRNA in duodenums of TRPV5+/+ and TRPV5–/– mice, assessed by quantitative real-time PCR analysis and calculated as a ratio to the HPRT RNA (n = 9).