Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport

• DOI: 10.1371/journal.pone.0147845
• Publication Date: 2016-02-03T13:55:56Z
• Authors: Xiaobin Han; Jiancheng Yang; Linqiang Li; Jinsong Huang; Gwendalyn King; L. Darryl Quarles
• Keywords: Hypophosphatemia; Science; Hypercalciuria; Bone and Bones; Kidney Tubules, Proximal; Mice; 03 medical and health sciences; Animals; Kidney Tubules, Distal; Klotho Proteins; Glucuronidase; Mice, Knockout; 0303 health sciences; Ion Transport; Q; R; Calcinosis; Biological Transport; Fibroblast Growth Factors; Hyperphosphatemia; Mice, Inbred C57BL; Fibroblast Growth Factor-23; Medicine; Calcium; Calcium Channels; Gene Deletion; Research Article

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.