Conditional deletion of Fgfr1 in the proximal and distal tubule identifies distinct roles in phosphate and calcium transport

Xiaobin Han, Jiancheng Yang, Linqiang Li, Jinsong Huang, Gwendalyn King, Leigh Quarles

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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.

Original languageEnglish (US)
Article numbere0147845
JournalPLoS One
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2016

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Receptor, Fibroblast Growth Factor, Type 1
phosphates
calcium
mice
fibroblast growth factors
Phosphates
Kidney
kidneys
Symporters
Phosphate Transport Proteins
gamma-Glutamyltransferase
Hyperphosphatemia
Hypophosphatemia
Hypercalciuria
spina bifida
Spinal Dysraphism
Parathyroid Hormone
symporters
proximal tubules
gamma-glutamyltransferase

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Conditional deletion of Fgfr1 in the proximal and distal tubule identifies distinct roles in phosphate and calcium transport. / Han, Xiaobin; Yang, Jiancheng; Li, Linqiang; Huang, Jinsong; King, Gwendalyn; Quarles, Leigh.

In: PLoS One, Vol. 11, No. 2, e0147845, 01.02.2016.

Research output: Contribution to journalArticle

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