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Aldosterone and ENaC: From Genetics to Physiology
Physiologisches Institut, University of Würzburg, 97070 Wurzburg, Germany
Submitted 29 October 2003 ; accepted in final form 21 January 2004
Aldosterone enhances Na+ reabsorption via epithelial Na+ channels (ENaC). Aldosterone also stimulates the protein kinase ERK1/2- and the epidermal growth factor (EGF) receptor (EGFR)-signaling pathway. Yet EGF and ERK1/2 are known inhibitors of ENaC-mediated Na+ reabsorption. In the present study, using the well-established Madin-Darby canine kidney C7 cell line, we tested the hypothesis that EGFR represents a negative-feedback control for chronic aldosterone-induced Na+ reabsorption [amiloride-inhibitable short-circuit current (Isc)]. Mineralocorticoid receptor expression was confirmed by RT-PCR and Western blot analysis. Aldosterone enhanced ERK1/2 phosphorylation in an EGFR-dependent way. Furthermore, aldosterone stimulated EGFR expression. Aldosterone (10 nmol/l) induced a small transient increase in Isc under control conditions. Inhibition of ERK1/2 phosphorylation with U-0126 (10 µmol/l) stimulated Isc, indicating constitutive ENaC inhibition. Aldosterone exerted a significantly larger effect in the presence of U-0126 than without U-0126. EGF (10 µg/l) inhibited Isc, whereas inhibition of EGFR kinase by tyrphostin AG-1478 (100 nmol/l) enhanced Isc. Aldosterone was more effective in the presence of AG-1478 than without AG-1478. In summary, we propose that the EGFR-signaling cascade can serve as a negative-feedback control to limit the effect of aldosterone-induced Na+ reabsorption.
extracellular signal-regulated kinase 1/2; Madin-Darby canine kidney C7 cells
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