title: Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice.
abstract: In the present study, we evaluated the roles of type II and type III sodium-dependent P(i) 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 P(i) transporter (PiT2) protein, and renal Na/P(i) 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)(2)D(3) 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 P(i) 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)(2)D(3). 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 P(i) homeostasis.
authors.affiliation: Department of Molecular Nutrition, Institution of Health Biosciences, University of Tokushima Graduate School, Kuramoto-Cho, Tokushima, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tomoe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Segawa
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Shiozawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.forename: Rieko
authors.initials: R
authors.lastname: Tominaga
authors.forename: Etsuyo
authors.initials: E
authors.lastname: Hanabusa
authors.forename: Fumito
authors.initials: F
authors.lastname: Aranami
authors.forename: Junya
authors.initials: J
authors.lastname: Furutani
authors.forename: Shoji
authors.initials: S
authors.lastname: Kuwahara
authors.forename: Sawako
authors.initials: S
authors.lastname: Tatsumi
authors.forename: Mitsutu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ito
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006801:Humans; D017674:Hypophosphatemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D007015:Hypophosphatemia, Familial / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010710:Phosphates / Q000097:blood; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000172:deficiency* / Q000235:genetics; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000378:metabolism; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000172:deficiency* / Q000235:genetics
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C493565:Slc20a2 protein, mouse; C493555:Slc34a1 protein, mouse; C493558:Slc34a2 protein, mouse; C493563:Slc34a3 protein, mouse; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002117:Calcitriol; D002118:Calcium