title: Biphasic regulation of ENaC by TGF-{alpha} and EGF in renal epithelial cells.
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.
authors.affiliation: Emory Univ. School of Medicine, Department of Physiology, Whitehead Bldg., Rm. 655, Atlanta, GA 30322, USA. lliu6@emory.edu
authors.forename: Lian
authors.initials: L
authors.lastname: Liu
authors.forename: Billie Jeanne
authors.initials: BJ
authors.lastname: Duke
authors.forename: Bela
authors.initials: B
authors.lastname: Malik
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yue
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D007668:Kidney / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects; D021122:Protein Subunits; D012964:Sodium / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D021122:Protein Subunits; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D012964:Sodium