title: Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4.
abstract: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂ Vitamin D₃]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1-4 with "b" and "c" isoforms for receptors 1, 2, and 3. FGFR1, 3, and 4 are expressed in the mouse proximal tubule, and deletion of any one receptor did not affect serum phosphate levels, suggesting that more than one receptor is involved in mediating the phosphaturic actions of FGF23. To determine the receptors responsible for the phosphaturic actions of FGF23, we studied Fgfr1 (kidney conditional) and Fgfr4 (global) double mutant mice (Fgfr1⁻/⁻/Fgfr4⁻/⁻). Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have higher FGF23 levels than their wild-type counterparts (108.1 ± 7.3 vs. 4,953.6 ± 675.0 pg/ml; P < 0.001). Despite the elevated FGF23 levels, Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have elevated serum phosphorus levels, increased brush-border membrane vesicle (BBMV) phosphate transport, and increased Na-P(i) cotransporter 2c (NaPi-2c) protein expression compared with wild-type mice. These data are consistent with FGFR1 and FGFR4 being the critical receptors for the phosphaturic actions of FGF23.
authors.affiliation: Dept. of Pediatrics, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX. Jyothsna.Gattineni@UTSouthwestern.edu.
authors.forename: Jyothsna
authors.initials: J
authors.lastname: Gattineni
authors.forename: Priyatharshini
authors.initials: P
authors.lastname: Alphonse
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Nisha
authors.initials: N
authors.lastname: Mathews
authors.forename: Carlton M
authors.initials: CM
authors.lastname: Bates
authors.forename: Michel
authors.initials: M
authors.lastname: Baum
mesh_terms: D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005966:Glucuronidase / Q000096:biosynthesis; D054559:Hyperphosphatemia; D017674:Hypophosphatemia; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D000090265:Klotho Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008871:Microvilli / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000096:biosynthesis; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
chemical_list: C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: FGF receptors; fibroblast growth factor 23; phosphate; proximal tubule; vitamin D