Aldosterone Stimulates Epidermal Growth Factor Receptor Expression*
- Alexander W. Krug‡§,
- Claudia Grossmann‡§,
- Claudia Schuster‡,
- Ruth Freudinger‡,
- Sigrid Mildenberger‡,
- Manjapra V. Govindan¶ and
- Michael Gekle‡**
- ‡Physiologisches Institut der Universität Würzburg, Würzburg 97070, Germany and ¶Centré de Recherche, L′Hotel-Dieu de Québec, University Laval, Québec G1R 2J6, Canada
- ** To whom correspondence should be addressed: Professor of Physiology, Physiologisches Institut, Universität Würzburg, Röntgenring 9, 97070 Würzburg. Tel.: 0931-312739; Fax: 0931-312741; E-mail: michael.gekle{at}mail.uni-wuerzburg.de.
Abstract
The steroid hormone aldosterone plays an important role during pathological tissue modifications, similar to cardiovascular or renal fibrosis. The underlying mechanisms for the pathological actions are not understood. Interaction of aldosterone with the epidermal growth factor (EGF) receptor is an attractive hypothesis to explain pathological tissue remodeling elicited by aldosterone, because (i) mineralocorticoids can sensitize cells for EGF, (ii) mineralocorticoid receptor (MR)-antagonists reduce EGFR-mRNA expression, (iii) EGFR itself supports the development of cardiovascular or renal fibrosis, and (iv) signaling elements involved in the pathological action of aldosterone (similar to ERK1/2 or NFkB) are typical downstream modules during EGF signaling. In addition, an interaction of aldosterone and EGF with respect to ERK1/2 activation has been described. Here we show that aldosterone stimulates EGFR expression in renal tissue of adrenalectomized rats and in human renal primary cell cultures. Furthermore, Chinese hamster ovary (CHO) cells normally devoid of EGFR or MR express EGFR after transfection with human MR (CHO-MR cells) but not after transfection with human glucocorticoid receptor (CHO-GR cells). In CHO-MR cells, EGFR-expression is up-regulated by aldosterone and inhibited by spironolactone. CHO-MR cells but not CHO-GR cells respond with ERK1/2 phosphorylation to EGF exposure. The responsiveness to other peptide hormones was virtually not affected. These data suggest that EGFR is an aldosterone-induced protein and is involved in the manifold (patho)biological actions of aldosterone.
Footnotes
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↵1 The abbreviations used are: MR, mineralocorticoid receptor; ADX, adrenalectomized; Aldo, aldosterone; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; GR, glucocorticoid receptor; PMA, phorbol 12-myristate 13-acetate; MDCK, Madin-Darby canine kidney cells; PBS, phosphate-buffered saline; Luc, luciferase; ANOVA, analysis of variance; hMR, human MR; hGR, human GR; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase.
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↵* This study was supported by the Deutsche Forschungsgemeinschaft (Grants Ge 905/4–2 and 4–3). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Both authors contributed equally to this work.
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- Received July 25, 2003.
- Revision received August 21, 2003.
- The American Society for Biochemistry and Molecular Biology, Inc.
