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1 Physiologisches Institut, University of Wuerzburg, Wuerzburg, Germany
* To whom correspondence should be addressed. E-mail: michael.gekle{at}mail.uni-wuerzburg.de.
Aldosterone enhances Na+-reabsorption via epithelial Na+-channels (ENaC). It has been shown that aldosterone also stimulates the protein kinase ERK1/2 and the epidermal growth factor receptor (EGFR) signaling pathway. Yet, EGF and ERK1/2 are known inhibitors of ENaC-mediated Na+-reabsorption. In the present study we tested the hypothesis that EGFR represents a negative feed-back control for chronic aldosterone-induced Na+-reabsorption (amiloride-inhibitable Isc) using the well established MDCK-C7 cell line. Mineralocorticoid receptor expression was confirmed by RT-PCR and Western Blot. Aldosterone enhanced ERK1/2-phosphorylation in a EGFR-dependent way. Furthermore, aldosterone stimulated EGFR-expression. 10 nmol/l aldosterone induced a small transient increase in Isc under control conditions. Inhibition of ERK1/2-phosphorylation with U0126 (10 µmol/l) stimulated Isc, indicating constitutive ENaC-inhibition. In the presence of U0126 aldosterone extered a significantly larger effect as compared to control. EGF (10 µg/l) inhibited Isc, whereas inhibition of EGFR-kinase (100 nmol/l tyrphostin AG1478) enhanced Isc. In the presence of AG 1478, aldosterone was more effective as compared to control. In summary, we would like to propose that the EGFR signaling cascade can serve as a negative feed-back control to limit the effect of aldosterone-induced Na+-reabsorption.
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