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+(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-D9Kincreased. In the kidney, klotho-/-mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D28K, 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-α-hydroxylase (1αOHase), and calbindin-D9Kexcluded 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

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Persistent URL dx.doi.org/10.1681/ASN.2008121273, hdl.handle.net/1765/25410
Alexander, R.T, Woudenberg-Vrenken, T.E, Buurman, J, Dijkman, H, van der Eerden, B.C.J, van Leeuwen, J.P.T.M, … Hoenderop, J.G. (2009). Klotho prevents renal calcium loss. American Society of Nephrology. Journal, 20(11), 2371–2379. doi:10.1681/ASN.2008121273