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Klotho Prevents Renal Calcium Loss

R. Todd Alexander^*,, Titia E. Woudenberg-Vrenken^*, Jan Buurman^*, Henry Dijkman, Bram C. J. van der Eerden, Johannes P.T.M. van Leeuwen, René J. Bindels^* and Joost G. Hoenderop^*

*Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands;
Department of Pediatrics, University of Alberta, Alberta, Canada;
Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence: Dr. Joost G. Hoenderop, 286 Physiology, Radboud University, Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3610580; Fax: 31-24-3616413; E-mail: J.Hoenderop{at}fysiol.umcn.nl

Received for publication December 17, 2008. Accepted for publication July 10, 2009.

Disturbed calcium (Ca²⁺) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin D metabolism, but alternative possibilities exist. We hypothesized that failed tubular Ca²⁺ absorption is primary, which causes increased urinary Ca²⁺ excretion, leading to elevated 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and its sequelae. Here, we assessed intestinal Ca²⁺ absorption, bone densitometry, renal Ca²⁺ excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho^–/– mice. We observed elevated serum Ca²⁺ and fractional excretion of Ca²⁺ (FE_Ca) in klotho^–/– mice. Klotho^–/– mice also showed intestinal Ca²⁺ hyperabsorption, osteopenia, and renal precipitation of calcium-phosphate. Duodenal mRNA levels of transient receptor potential vanilloid 6 (TRPV6) and calbindin-D_9K increased. In the kidney, klotho^–/– mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D_28K, implying a failure to absorb Ca²⁺ through the distal convoluted tubule/connecting tubule (DCT/CNT) via TRPV5. Gene and protein expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D-1--hydroxylase (1OHase), and calbindin-D_9K excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca²⁺ wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca²⁺ handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca²⁺ loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673