FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway

Bone. 2012 Sep;51(3):621-8. doi: 10.1016/j.bone.2012.05.015. Epub 2012 May 27.

Abstract

Fibroblast growth factor-23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis which inhibits renal tubular phosphate reabsorption. Binding of circulating FGF23 to FGF receptors in the cell membrane requires the concurrent presence of the co-receptor αKlotho. It is still controversial whether αKlotho is expressed in the kidney proximal tubule, the principal site of phosphate reabsorption. Hence, it has remained an enigma as to how FGF23 downregulates renal phosphate reabsorption. Here, we show that renal proximal tubular cells do express the co-receptor αKlotho together with cognate FGF receptors, and that FGF23 directly downregulates membrane expression of the sodium-phosphate cotransporter NaPi-2a by serine phosphorylation of the scaffolding protein Na(+)/H(+) exchange regulatory cofactor (NHERF)-1 through ERK1/2 and serum/glucocorticoid-regulated kinase-1 signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Activation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / pharmacology*
  • Gene Expression Regulation / drug effects
  • Glucuronidase / genetics
  • Glucuronidase / metabolism
  • Humans
  • Hypophosphatemia, Familial / enzymology*
  • Hypophosphatemia, Familial / pathology*
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / enzymology*
  • Kidney Tubules, Proximal / pathology
  • Klotho Proteins
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Sodium-Hydrogen Exchangers / metabolism
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / metabolism

Substances

  • FGF23 protein, human
  • Fgf23 protein, mouse
  • Immediate-Early Proteins
  • Phosphoproteins
  • Sodium-Hydrogen Exchangers
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • sodium-hydrogen exchanger regulatory factor
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Glucuronidase
  • Klotho Proteins