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Published ahead of print on April 8, 2009
J Am Soc Nephrol 20: 955-960, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008070783
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Initial FGF23-Mediated Signaling Occurs in the Distal Convoluted Tubule

Emily G. Farrow, Siobhan I. Davis, Lelia J. Summers and Kenneth E. White

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 {alpha}-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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B. S. Levine, C. R. Kleeman, and A. J. Felsenfeld
The Journey From Vitamin D-Resistant Rickets to the Regulation of Renal Phosphate Transport
Clin. J. Am. Soc. Nephrol., November 1, 2009; 4(11): 1866 - 1877.
[Abstract] [Full Text] [PDF]


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