Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice

Daniel Ranch, Martin Y.H. Zhang, Anthony A. Portale, Farzana Perwad

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

In X-linked hypophosphatemia (XLH) and in its murine homologue, the Hyp mouse, increased circulating concentrations of fibroblast growth factor 23 (FGF-23) are critical to the pathogenesis of disordered metabolism of phosphate (Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. In this study, we hypothesized that in Hyp mice, FGF-23-mediated suppression of renal 1,25(OH)2D production and Pi reabsorption depends on activation of mitogen-activated protein kinase (MAPK) signaling. Wild-type and Hyp mice were administered either vehicle or the MEK inhibitor PD0325901 (12.5mg/kg) orally daily for 4 days. At baseline, the renal abundance of early growth response 1 (egr1) mRNA was approximately 2-fold greater in Hyp mice than in wild-type mice. Treatment with PD0325901 greatly suppressed egr1 mRNA abundance in both wild-type and Hyp mice. In Hyp mice, PD0325901 induced an 8-fold increase in renal 1α-hydroxylase mRNA expression and a 4-fold increase in serum 1,25(OH)2D concentrations compared with vehicle-treated Hyp mice. Serum Pi levels in Hyp mice increased significantly after treatment with PD0325901, and the increase was associated with increased renal Npt2a mRNA abundance and brush-border membrane Npt2a protein expression. These findings provide evidence that in Hyp mice, MAPK signaling is constitutively activated in the kidney and support the hypothesis that the FGF-23-mediated suppression of renal 1,25(OH)2D production and Pi reabsorption depends on activation of MAPK signaling via MEK/ERK1/2. These findings demonstrate the physiologic importance of MAPK signaling in the actions of FGF-23 in regulating renal 1,25(OH)2D and Pi metabolism.

Original languageEnglish (US)
Pages (from-to)1883-1890
Number of pages8
JournalJournal of Bone and Mineral Research
Volume26
Issue number8
DOIs
StatePublished - Aug 2011

Keywords

  • 1,25(OH)D
  • FGF-23
  • MAPK
  • XLH
  • phosphate

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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