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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/F282    most recent 90742.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by Gattineni, J. Articles by Baum, M. PubMed PubMed Citation Articles by Gattineni, J. Articles by Baum, M.

FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1

Departments of ¹Pediatrics and ²Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; ³Center for Cell and Developmental Biology, The Research Institute at Nationwide Children's Hospital, Columbus; ⁴Department of Zoology, Miami University, Oxford, Ohio; and ⁵Department of Pharmacology, New York University School of Medicine, New York, New York

Submitted 12 December 2008 ; accepted in final form 4 June 2009

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, –3, and –4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3^–/– and FGFR4^–/– null mice, and in conditional FGFR1^–/– mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1^–/–, FGFR3^–/–, and FGFR4^–/– mice and their wild-type counterparts. Administration of FGF23 to FGFR3^–/– mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4^–/– mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1^–/– mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

phosphaturia; phosphorus; proximal tubule