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- Title
Characterization of vitamin D-deficient klotho−/− mice: do increased levels of serum 1,25(OH)2D3 cause disturbed calcium and phosphate homeostasis in klotho−/− mice?
- Authors
Woudenberg-Vrenken, Titia E.; van der Eerden, Bram C.J.; van der Kemp, AnneMiete W.C.M.; van Leeuwen, Johannes P.T.M.; Bindels, René J.M.; Hoenderop, Joost G.J.
- Abstract
Background Klotho−/− mice display disturbed Ca2+ and vitamin D homeostasis. Renal cytochrome p450 27b1 (Cyp27b1), the enzyme that catalyzes the hydrolysis to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is increased in klotho−/− mice, and a 1,25(OH)2D3-deficient diet partially normalized Ca2+ homeostasis in these klotho−/− mice. The aim of the present study was to further delineate the interplay between 1,25(OH)2D3 and klotho and their relative contribution to the Ca2+ homeostasis of klotho−/− mice. Methods Double-klotho−/−/Cyp27b1−/− mice were generated and mice aged 8–12 weeks were housed in metabolic cages to collect 24-h urine. Blood samples were taken and the animals were sacrificed, and the kidney and duodenum tissues were sampled for RNA extraction. The bone was fixed in 10% v/v formalin and analysed by microcomputed tomography (μCT) scans. Results Klotho−/−/Cyp27b1−/− mice, like Cyp27b1−/− mice, displayed significantly decreased serum total calcium concentrations compared with wild-type mice (1.44 ± 0.03 and 2.25 ± 0.02 mM) along with normal urinary total calcium excretion. Hyperphosphataemia of klotho−/− mice normalized to wild-type levels in klotho−/−/Cyp27b1−/− mice. The mRNA levels of duodenal transient receptor potential vanilloid subtype 6 (TRPV6) and calcium-binding protein-D9K, and renal calbindin-D28K and NCX1 were significantly reduced in the double knockouts compared with wild-type or klotho−/− mice. Elevated TRPV5 protein levels in klotho−/− mice normalized to wild type in klotho−/−/Cyp27b1−/− mice, but were decreased in Cyp27b1−/− mice. μCT scans showed that klotho−/−/Cyp27b1−/− mice, as Cyp27b1−/− mice, display significant bone hypomineralization and severely decreased bone mass. Klotho−/− mice show a reduced bone mass and increased trabecular numbers. Conclusions Klotho−/−/Cyp27b1−/− mice resemble Cyp27b1−/− mice. Since 1,25(OH)2D3 is absent in these mice, our results imply that Ca2+ homeostasis in klotho−/− mice is affected by their excessive 1,25(OH)2D3 levels.
- Subjects
VITAMIN D deficiency; HOMEOSTASIS; DIAGNOSTIC imaging; OLD age; PHYSIOLOGY
- Publication
Nephrology Dialysis Transplantation, 2012, Vol 27, Issue 11, p4061
- ISSN
0931-0509
- Publication type
Article
- DOI
10.1093/ndt/gfs177