Details

Autor(en) / Beteiligte

• Grossmann, Claudia
• Freudinger, Ruth
• Mildenberger, Sigrid
• Krug, Alexander W
• Gekle, Michael

Titel

Evidence for epidermal growth factor receptor as negative-feedback control in aldosterone-induced Na+ reabsorption

Ist Teil von

• American journal of physiology. Renal physiology, 2004-06, Vol.286 (6), p.F1226-F1231

Ort / Verlag

United States

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (I(sc))]. 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 I(sc) under control conditions. Inhibition of ERK1/2 phosphorylation with U-0126 (10 micromol/l) stimulated I(sc), indicating constitutive ENaC inhibition. Aldosterone exerted a significantly larger effect in the presence of U-0126 than without U-0126. EGF (10 microg/l) inhibited I(sc), whereas inhibition of EGFR kinase by tyrphostin AG-1478 (100 nmol/l) enhanced I(sc). 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.