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

PLoS One. 2016 Feb 3;11(2):e0147845. doi: 10.1371/journal.pone.0147845. eCollection 2016.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Bone and Bones / abnormalities
  • Calcinosis / genetics
  • Calcium / blood
  • Calcium / metabolism*
  • Calcium / urine
  • Calcium Channels / metabolism
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / metabolism
  • Gene Deletion
  • Glucuronidase / metabolism
  • Hypercalciuria / genetics
  • Hyperphosphatemia / genetics
  • Hypophosphatemia / genetics
  • Ion Transport / genetics
  • Kidney Tubules, Distal / physiopathology*
  • Kidney Tubules, Proximal / physiopathology*
  • Klotho Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Parathyroid Hormone / metabolism
  • Phosphates / blood
  • Phosphates / metabolism*
  • Phosphates / urine
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Spinal Dysraphism / genetics
  • TRPV Cation Channels / metabolism


  • Calcium Channels
  • Fgf23 protein, mouse
  • Parathyroid Hormone
  • Phosphates
  • TRPV Cation Channels
  • Trpv5 protein, mouse
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • Fgfr1 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 1
  • Glucuronidase
  • Klotho Proteins
  • Calcium