title: Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism.
abstract: 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.
authors.affiliation: Clinical Research Center, Sixth Floor, Novumhuset, Karolinska University Hospital in Huddinge, Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.forename: Karolina
authors.initials: K
authors.lastname: Lindberg
authors.forename: Risul
authors.initials: R
authors.lastname: Amin
authors.forename: Ting
authors.initials: T
authors.lastname: Jia
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.forename: Tobias E
authors.initials: TE
authors.lastname: Larsson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015870:Gene Expression; D018390:Gene Targeting; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D054559:Hyperphosphatemia / Q000235:genetics / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008903:Minerals / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood; D015398:Signal Transduction; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism
chemical_list: C000717428:Fgf23 protein, mouse; D008903:Minerals; D010281:Parathyroid Hormone; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium