Tags

Type your tag names separated by a space and hit enter

Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism.
J Am Soc Nephrol. 2012 Oct; 23(10):1641-51.JA

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+Show Affiliations

Clinical Research Center, Sixth Floor, Novumhuset, Karolinska University Hospital in Huddinge, Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22878961

Citation

Olauson, Hannes, et al. "Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism." Journal of the American Society of Nephrology : JASN, vol. 23, no. 10, 2012, pp. 1641-51.
Olauson H, Lindberg K, Amin R, et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. J Am Soc Nephrol. 2012;23(10):1641-51.
Olauson, H., Lindberg, K., Amin, R., Jia, T., Wernerson, A., Andersson, G., & Larsson, T. E. (2012). Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. Journal of the American Society of Nephrology : JASN, 23(10), 1641-51.
Olauson H, et al. Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism. J Am Soc Nephrol. 2012;23(10):1641-51. PubMed PMID: 22878961.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. AU - Olauson,Hannes, AU - Lindberg,Karolina, AU - Amin,Risul, AU - Jia,Ting, AU - Wernerson,Annika, AU - Andersson,Göran, AU - Larsson,Tobias E, Y1 - 2012/08/09/ PY - 2012/8/11/entrez PY - 2012/8/11/pubmed PY - 2012/12/14/medline SP - 1641 EP - 51 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 23 IS - 10 N2 - 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. SN - 1533-3450 UR - https://www.unboundmedicine.com/medline/citation/22878961/Targeted_deletion_of_Klotho_in_kidney_distal_tubule_disrupts_mineral_metabolism_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=22878961 DB - PRIME DP - Unbound Medicine ER -