Biphasic regulation of ENaC by TGF-{alpha} and EGF in renal epithelial cells

Am J Physiol Renal Physiol. 2009 Jun;296(6):F1417-27. doi: 10.1152/ajprenal.90337.2008. Epub 2009 Mar 18.

Abstract

The epithelial sodium channel (ENaC) is regulated by epidermal growth factor (EGF). We investigate whether ENaC is regulated by another EGF receptor (EGFR) ligand, transforming growth factor-alpha (TGF-alpha). We show that chronic (24 h) treatment with TGF-alpha inhibits ENaC in Xenopus laevis kidney cells 20 times more strongly than EGF. By using single-channel measurements, we show that TGF-alpha significantly reduces the number of ENaC per patch. The open probability (P(o)) is unchanged by 24-h treatment with TGF-alpha. alpha-, beta-, and gamma-ENaC mRNA levels are significantly reduced by TGF-alpha or EGF. TGF-alpha or EGF reduces alpha- and gamma-ENaC proteins in the membrane; however, beta-ENaC is unchanged. TGF-alpha or EGF inhibits ENaC by activating EGFR since the EGFR inhibitor AG1478 blocks the effects of both. The MAPK 1/2 inhibitor U0126 also blocks the effect of TGF-alpha or EGF on ENaC, indicating that the MAPK1/2 pathway is involved in the TGF-alpha- or EGF-induced inhibition of ENaC. Interestingly, acute treatment (<1 h) with TGF-alpha or EGF does not inhibit ENaC current; it enhances ENaC activity by increasing P(o). Pretreatment of the cells with U0126 potentiates the acute TGF-alpha- or EGF-induced stimulation of ENaC. This TGF-alpha- or EGF-induced increase in sodium current is abolished by a phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor, LY294002, suggesting that PI-3 kinase is involved in the activation of sodium transport. In conclusion, chronic treatment with TGF-alpha or EGF inhibits ENaC by decreasing the number of channels in the membrane transcriptionally through MAPK1/2 pathways, but acute treatment with TGF-alpha or EGF activates ENaC by increasing P(o) via PI-3 kinase.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / metabolism*
  • Epithelial Cells / metabolism*
  • Epithelial Sodium Channels / metabolism*
  • Kidney / cytology*
  • Membrane Potentials / drug effects
  • Protein Subunits
  • Sodium / metabolism
  • Transforming Growth Factor alpha / metabolism*
  • Xenopus laevis

Substances

  • Enzyme Inhibitors
  • Epithelial Sodium Channels
  • Protein Subunits
  • Transforming Growth Factor alpha
  • Epidermal Growth Factor
  • Sodium