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Initial FGF23-Mediated Signaling Occurs in the Distal Convoluted Tubule

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana

Correspondence: Dr. Kenneth E. White, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut Street, IB130, Indianapolis, IN 46202. Phone: 317-278-1775; Fax: 317-274-2293; E-mail: kenewhit{at}iupui.edu

Received for publication July 25, 2008. Accepted for publication November 19, 2008.

Fibroblast growth factor-23 (FGF23), a hormone central to phosphate and vitamin D metabolism, reduces renal absorption of phosphate by downregulating the sodium-phosphate cotransporter Npt2a. However, the mechanisms of FGF23 action in the kidney are unclear, as Npt2a localizes to the proximal tubule (PT) and the FGF23 coreceptor -Klotho (KL) localizes to the distal convoluted tubule (DCT). Immunofluorescent analyses following FGF23 injection in mice showed robust staining for phospho-ERK1/2, a marker of FGF23 bioactivity, only within the DCT in a subset of KL-positive cells. This activity colocalized with the FGF23 receptor FGFR1 and was present in DCT cells that were adjacent to Npt2a-expressing PT segments. Although KL is expressed as both secreted and membrane-bound isoforms, only the membrane-bound isoform was capable of mediating FGF23 bioactivity. These findings provide novel insight into the mechanisms of hormone-regulated phosphate metabolism by identifying an intrarenal signaling axis for FGF23.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673