Klotho prevents renal calcium loss.
Disturbed calcium (Ca(2+)) 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 Ca(2+) absorption is primary, which causes increased urinary Ca(2+) excretion, leading to elevated 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and its sequelae. Here, we assessed intestinal Ca(2+) absorption, bone densitometry, renal Ca(2+) excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho(-/-) mice. We observed elevated serum Ca(2+) and fractional excretion of Ca(2+) (FE(Ca)) in klotho(-/-) mice. Klotho(-/-) mice also showed intestinal Ca(2+) 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 Ca(2+) 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 (1alphaOHase), and calbindin-D(9K) excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca(2+) wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca(2+) handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca(2+) loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis.
Alexander
R Todd
RT
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, , 6500 HB Nijmegen, The Netherlands.
Woudenberg-Vrenken
Titia E
TE
Buurman
Jan
J
Dijkman
Henry
H
van der Eerden
Bram C J
BC
van Leeuwen
Johannes P T M
JP
Bindels
René J
RJ
Hoenderop
Joost G
JG
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains
D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium