Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism
Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism
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DOI：
10.1681/asn.2012010048
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发表时间：
2012-10-01
影响因子：
13.6
通讯作者：
Larsson, Tobias E.
中科院分区：
文献类型：
--
作者：
Olauson, Hannes;Lindberg, Karolina;Larsson, Tobias E.
Renal 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.
