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Klotho gene, phosphocalcic metabolism, and survival in dialysis.
J Ren Nutr. 2009 Jan; 19(1):50-6.JR

Abstract

The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress.

Authors+Show Affiliations

Service de Néphrologie et Dialyse, Clinique du Landy, Saint Ouen, France. urena.pablo@wanadoo.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19121771

Citation

Torres, Pablo Ureña, et al. "Klotho Gene, Phosphocalcic Metabolism, and Survival in Dialysis." Journal of Renal Nutrition : the Official Journal of the Council On Renal Nutrition of the National Kidney Foundation, vol. 19, no. 1, 2009, pp. 50-6.
Torres PU, Prié D, Beck L, et al. Klotho gene, phosphocalcic metabolism, and survival in dialysis. J Ren Nutr. 2009;19(1):50-6.
Torres, P. U., Prié, D., Beck, L., De Brauwere, D., Leroy, C., & Friedlander, G. (2009). Klotho gene, phosphocalcic metabolism, and survival in dialysis. Journal of Renal Nutrition : the Official Journal of the Council On Renal Nutrition of the National Kidney Foundation, 19(1), 50-6. https://doi.org/10.1053/j.jrn.2008.10.018
Torres PU, et al. Klotho Gene, Phosphocalcic Metabolism, and Survival in Dialysis. J Ren Nutr. 2009;19(1):50-6. PubMed PMID: 19121771.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Klotho gene, phosphocalcic metabolism, and survival in dialysis. AU - Torres,Pablo Ureña, AU - Prié,Dominique, AU - Beck,Laurent, AU - De Brauwere,David, AU - Leroy,Christine, AU - Friedlander,Gérard, PY - 2009/1/6/entrez PY - 2009/1/6/pubmed PY - 2009/5/16/medline SP - 50 EP - 6 JF - Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation JO - J Ren Nutr VL - 19 IS - 1 N2 - The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress. SN - 1532-8503 UR - https://www.unboundmedicine.com/medline/citation/19121771/Klotho_gene_phosphocalcic_metabolism_and_survival_in_dialysis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1051-2276(08)00451-2 DB - PRIME DP - Unbound Medicine ER -