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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Figure 4

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Bone phenotypes of female and male TRPV5+/+ and TRPV5–/– mice. (a) Repre...
Bone phenotypes of female and male TRPV5+/+ and TRPV5–/– mice. (a) Representative cross-sectional x-ray images of the femoral head (I), the lesser trochanter (II), and the diaphysis (III) in TRPV5+/+ and TRPV5–/– mice. Note the decreased cortical bone width in the trochanter and diaphysis (arrows). (b) MOI as a parameter of bone quality. (c) Three-dimensional reconstruction of femurs from TRPV5+/+ and TRPV5–/– mice. Note the reduced cortical and Tb.Th in TRPV5–/– mice. (d) Changes in serum levels of 1,25-(OH)2D3, PTH, and Ca2+ in TRPV5+/+, TRPV5+/–, and TRPV5–/– mice. Values are expressed as percentage of TRPV5+/+ values ± SEM. The absolute values for PTH are TRPV5+/+, 55 ± 15 pg/ml; TRPV5+/–, 59 ± 14 pg/ml; and TRPV5–/–, 60 ± 16 pg/ml; for 1,25-(OH)2D3, TRPV5+/+, 239 ± 38 pmol/l; TRPV5+/–, 225 ± 32 pmol/l; TRPV5–/–, 691 ± 88 pmol/l; and for free Ca2+ concentration, TRPV5+/+, 1.20 ± 0.02 mM; TRPV5+/–, 1.25 ± 0.03 mM; and TRPV5–/–, 1.20 ± 0.03 mM. *P < 0.05, significant difference from wild-type mice.