Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice

Y Tomoe, H Segawa, K Shiozawa… - American Journal …, 2010 - journals.physiology.org
Y Tomoe, H Segawa, K Shiozawa, I Kaneko, R Tominaga, E Hanabusa, F Aranami…
American Journal of Physiology-Renal Physiology, 2010journals.physiology.org
In the present study, we evaluated the roles of type II and type III sodium-dependent Pi
cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector
encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout
(KO) mice, Npt2c KO mice, and Npt2a−/− Npt2c−/− mice (DKO mice). In Npt2a KO mice,
FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c,
type III Na-dependent Pi transporter (PiT2) protein, and renal Na/Pi transport activity. In …
In the present study, we evaluated the roles of type II and type III sodium-dependent Pi cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a−/−Npt2c−/− mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent Pi transporter (PiT2) protein, and renal Na/Pi transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)2D3 levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein; 2) in DKO mice, renal Pi reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed; and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)2D3. These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic Pi homeostasis.
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