Open AccessConditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport
Author(s) -
Xiaobin Han,
Juhua Yang,
Linqiang Li,
Jinsong Huang,
Gwendalyn D. King,
L. Darryl Quarles
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0147845
Subject(s) - fibroblast growth factor 23 , fibroblast growth factor receptor 1 , hypophosphatemia , medicine , endocrinology , reabsorption , conditional gene knockout , fibroblast growth factor , hyperphosphatemia , parathyroid hormone , biology , hypercalciuria , kidney , calcium , chemistry , receptor , excretion , phenotype , biochemistry , kidney disease , gene
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 Fgfr1 flox/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 Fgfr1 PT-cKO and Fgfr1 DT-cKO , respectively). Fgfr1 PT-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, Fgfr1 DT-cKO mice unexpectedly developed hypercalciuria, secondary elevations of parathyroid hormone (PTH), hypophosphatemia and enhanced urinary phosphate excretion. Fgfr1 PT-cKO mice also developed a curly tail/spina bifida-like skeletal phenotype, whereas Fgfr1 DT-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.