title: Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells.
abstract: Isoforms of the mammalian klotho protein serve as membrane co-receptors that regulate renal phosphate and calcium reabsorption. Phosphaturic effects of klotho are mediated in cooperation with fibroblast growth factor receptor-1 and its FGF23 ligand. The vitamin D receptor and its 1,25-dihydroxyvitamin D(3) ligand are also crucial for calcium and phosphate regulation at the kidney and participate in a feedback loop with FGF23 signaling. Herein we characterize vitamin D receptor-mediated regulation of klotho mRNA expression, including the identification of vitamin D responsive elements (VDREs) in the vicinity of both the mouse and human klotho genes. In keeping with other recent studies of vitamin D-regulated genes, multiple VDREs control klotho expression, with the most active elements located at some distance (-31 to -46 kb) from the klotho transcriptional start site. We therefore postulate that the mammalian klotho gene is up-regulated by liganded VDR via multiple remote VDREs. The phosphatemic actions of 1,25-dihydroxyvitamin D(3) are thus opposed via the combined phosphaturic effects of FGF23 and klotho, both of which are upregulated by the liganded vitamin D receptor.
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA. phxryan@gmail.com
authors: Ryan E
authors: RE
authors: Forster
authors: Peter W
authors: PW
authors: Jurutka
authors: Jui-Cheng
authors: JC
authors: Hsieh
authors: Carol A
authors: CA
authors: Haussler
authors: Christine L
authors: CL
authors: Lowmiller
authors: Ichiro
authors: I
authors: Kaneko
authors: Mark R
authors: MR
authors: Haussler
authors: G
authors: G
authors: Kerr Whitfield
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D008024:Ligands; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D030181:Vitamin D Response Element
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D008024:Ligands; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins