Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells

Ryan E. Forster, Peter Jurutka, Jui Cheng Hsieh, Carol A. Haussler, Christine L. Lowmiller, Ichiro Kaneko, Mark R. Haussler, G. Kerr Whitfield

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


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 -46kb) 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.

Original languageEnglish (US)
Pages (from-to)557-562
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number3
StatePublished - Oct 28 2011


  • Aging
  • Fibroblast growth factor 23
  • Kidney tubules, collecting
  • Kidney tubules, distal
  • Kidney tubules, proximal
  • Klotho protein
  • RNA splicing
  • Receptors, calcitriol
  • Response elements
  • Vitamin D

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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