Submitted on December 12, 2008
Revised on May 19, 2009
Accepted on June 4, 2009
FGF23 Decreases Renal NaPi-2a and NaPi-2c Expression and Induces Hypophosphatemia In Vivo Predominantly Via FGF Receptor 1
Jyothsna Gattineni1, Carlton Bates2, Katherine Twombley1, Vangipuram Dwarakanath1, Michael L Robinson3, Regina Goetz4, Moosa Mohammadi4, and Michel Baum5*
1 UT Southwestern
2 Columbus Children's Hospital
3 Miami University
4 New York University School of Medicine
5 Univ. of Texas / Southwestern Med Ctr
* To whom correspondence should be addressed. E-mail: michel.baum{at}utsouthwestern.edu.
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 co-transporters (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 mediate 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. Likewise 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.
