Klotho Prevents Renal Calcium Loss

RT Alexander, TE Woudenberg-Vrenken, J Buurman, H Dijkman, Bram van der Eerden, Hans van Leeuwen, RJ Bindels, JG Hoenderop

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Disturbed calcium (Ca2+) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin ID 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 D-3 [1,25(OH)(2)D-3] 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+ (FECa) 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-alpha-hydroxylase (1 alpha OHase), 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.
Original languageUndefined/Unknown
Pages (from-to)2371-2379
Number of pages9
JournalJournal of the American Society of Nephrology
Issue number11
Publication statusPublished - 2009

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  • EMC MM-01-39-02

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