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Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism Olauson H; Lindberg K; Amin R; Jia T; Wernerson A; Andersson G; Larsson TEJ Am Soc Nephrol 2012[Oct]; 23 (10): 1641-51Renal Klotho controls mineral metabolism by directly modulating tubular reabsorption of phosphate and calcium and by acting as a co-receptor for the phosphaturic and vitamin D-regulating hormone fibroblast growth factor-23 (FGF23). Klotho null mice have a markedly abnormal phenotype. We sought to determine effects of renal-specific and partial deletion of Klotho to facilitate investigation of its roles in health and disease. We generated a mouse model with partial deletion of Klotho in distal tubular segments (Ksp-KL(-/-)). In contrast to Klotho null mice, Ksp-KL(-/-) mice were fertile, had a normal gross phenotype, and did not have vascular or tubular calcification on renal histology. However, Ksp-KL(-/-) mice were hyperphosphatemic with elevated FGF23 levels and abundant expression of the sodium-phosphate cotransporter Npt2a at the brush border membrane. Serum calcium and 1,25-dihydroxyvitamin D(3) levels were normal but parathyroid hormone levels were decreased. TRPV5 protein was reduced with a parallel mild increase in urinary calcium excretion. Renal expression of vitamin D regulatory enzymes and vitamin D receptor was higher in Ksp-KL(-/-) mice than controls, suggesting increased turnover of vitamin D metabolites and a functional increase in vitamin D signaling. There was a threshold effect of residual renal Klotho expression on FGF23: deletion of >70% of Klotho resulted in FGF23 levels 30-250 times higher than in wild-type mice. A subgroup of Ksp-KL(-/-) mice with normal phosphate levels had elevated FGF23, suggesting a Klotho-derived renal-bone feedback loop. Taken together, renal FGF23-Klotho signaling, which is disrupted in CKD, is essential for homeostatic control of mineral metabolism.|Animals[MESH]|Calcium/metabolism[MESH]|Female[MESH]|Fibroblast Growth Factor-23[MESH]|Fibroblast Growth Factors/metabolism[MESH]|Gene Expression[MESH]|Gene Targeting[MESH]|Glucuronidase/*deficiency/genetics/metabolism[MESH]|Homeostasis[MESH]|Hyperphosphatemia/genetics/metabolism[MESH]|Kidney Tubules, Distal/*metabolism[MESH]|Klotho Proteins[MESH]|Male[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Minerals/*metabolism[MESH]|Parathyroid Hormone/blood[MESH]|Signal Transduction[MESH]|Sodium-Phosphate Cotransporter Proteins, Type IIa/metabolism[MESH]|Vitamin D/metabolism[MESH] |
