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.
Highlights
There are 22 mammalian fibroblastic growth factors (FGFs) subgrouped into 7 subfamilies and four alternative spliced FGF receptor genes (FGFR1-FGFR4) that encode seven membraneassociated tyrosine kinase isoforms (FGFRs 1 b, 1c, 2b, 2c, 3b, 3c and 4)
We found γGT-Cre and kidney specific-Cre (Ksp-Cre) excision of the Fgfr1 floxed alleles occurred in the kidney in both Fgfr1PT-cKO mice (Fig 1B) and Fgfr1DT-cKO mice (Fig 1C)
We examined the effects of distal tubule deletion of fibroblast growth factor receptor-1 (FGFR1) on renal tubular transporters involved in calcium transport (Fig 5E–5J)
Summary
There are 22 mammalian fibroblastic growth factors (FGFs) subgrouped into 7 subfamilies and four alternative spliced FGF receptor genes (FGFR1-FGFR4) that encode seven membraneassociated tyrosine kinase isoforms (FGFRs 1 b, 1c, 2b, 2c, 3b, 3c and 4). The more recently evolved subfamily of hormonal FGFs, include FGF-19, FGF-21 and FGF-23, have N-terminal FGF-homology domains linked to novel C-. Hormonal FGFs have defined novel endocrine networks and brought new attention to the postnatal functions of FGFR signaling. One of these is the bone-kidney endocrine network, where FGF-23 produced by osteoblasts and osteocytes in bone regulates proximal (PT) and distal tubular (DT) functions in the adult kidney [1, 4,5,6,7,8]. More recent studies indicate that FGF-23 has distal tubular functions that include stimulation of renal sodium and calcium retention [10,11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
