title: Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport.
abstract: A postnatal role of fibroblast growth factor receptor-1 (FGFR1) in the kidney is suggested by its binding to α-Klotho to form an obligate receptor for the hormone fibroblast growth factor-23 (FGF-23). FGFR1 is expressed in both the proximal and distal renal tubular segments, but its tubular specific functions are unclear. In this study, we crossed Fgfr1flox/flox mice with either gamma-glutamyltransferase-Cre (γGT-Cre) or kidney specific-Cre (Ksp-Cre) mice to selectively create proximal tubule (PT) and distal tubule (DT) Fgfr1 conditional knockout mice (designated Fgfr1PT-cKO and Fgfr1DT-cKO, respectively). Fgfr1PT-cKO mice exhibited an increase in sodium-dependent phosphate co-transporter expression, hyperphosphatemia, and refractoriness to the phosphaturic actions of FGF-23, consistent with a direct role of FGFR1 in mediating the proximal tubular phosphate responses to FGF-23. In contrast, Fgfr1DT-cKO mice unexpectedly developed hypercalciuria, secondary elevations of parathyroid hormone (PTH), hypophosphatemia and enhanced urinary phosphate excretion. Fgfr1PT-cKO mice also developed a curly tail/spina bifida-like skeletal phenotype, whereas Fgfr1DT-cKO mice developed renal tubular micro-calcifications and reductions in cortical bone thickness. Thus, FGFR1 has dual functions to directly regulate proximal and distal tubule phosphate and calcium reabsorption, indicating a physiological role of FGFR1 signaling in both phosphate and calcium homeostasis.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Linqiang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Huang
authors.affiliation: University of Alabama in Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Gwendalyn
authors.initials: G
authors.lastname: King
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities; D002114:Calcinosis / Q000235:genetics; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D015220:Calcium Channels / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D017353:Gene Deletion; D005966:Glucuronidase / Q000378:metabolism; D053565:Hypercalciuria / Q000235:genetics; D054559:Hyperphosphatemia / Q000235:genetics; D017674:Hypophosphatemia / Q000235:genetics; D017136:Ion Transport / Q000235:genetics; D007686:Kidney Tubules, Distal / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000503:physiopathology*; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D016135:Spinal Dysraphism / Q000235:genetics; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium
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