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

Liu L, Duke BJ, Malik B, Yue Q, Eaton DC,. Biphasic regulation of ENaC by TGFand EGF in renal epithelial cells. Am J Physiol Renal Physiol 296: F1417–F1427, 2009. First published March 18, 2009; doi:10.1152/ajprenal.90337.2008.—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(TGF). We show that chronic (24 h) treatment with TGFinhibits ENaC in Xenopus laevis kidney cells 20 times more strongly than EGF. By using single-channel measurements, we show that TGFsignificantly reduces the number of ENaC per patch. The open probability (Po) is unchanged by 24-h treatment with TGF. -, -, and -ENaC mRNA levels are significantly reduced by TGFor EGF. TGFor EGF reduces and -ENaC proteins in the membrane; however, -ENaC is unchanged. TGFor 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 TGFor EGF on ENaC, indicating that the MAPK1/2 pathway is involved in the TGFor EGF-induced inhibition of ENaC. Interestingly, acute treatment ( 1 h) with TGFor EGF does not inhibit ENaC current; it enhances ENaC activity by increasing Po. Pretreatment of the cells with U0126 potentiates the acute TGFor EGF-induced stimulation of ENaC. This TGFor 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 TGFor EGF inhibits ENaC by decreasing the number of channels in the membrane transcriptionally through MAPK1/2 pathways, but acute treatment with TGFor EGF activates ENaC by increasing Po via PI-3 kinase.