Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter
Ist Teil von
American journal of physiology: endocrinology and metabolism, 2007-06, Vol.292 (6), p.E1790-E1800
Ort / Verlag
United States: American Physiological Society
Erscheinungsjahr
2007
Quelle
MEDLINE
Beschreibungen/Notizen
1 Physiologisches Institut der Universitaet Wuerzburg, Wuerzburg; and 2 Universitaetsklinikum Carl Gustav Carus Universitaet Dresden, Medical Clinic III, Dresden, Germany
Submitted 22 December 2006
; accepted in final form 15 February 2007
Aldosterone plays a key role in cardiovascular and renal injury. The underlying mechanisms are not completely understood. Because the epidermal growth factor receptor (EGFR) is involved in the development of fibrosis and vascular dysfunction, upregulation of EGFR expression by aldosterone-bound mineralocorticoid receptor (MR) is an attractive hypothesis. We investigated the effect of aldosterone on EGFR expression in the aorta of adrenalectomized rats and in human aorta smooth muscle cells (HAoSMC) in primary culture. Aldosterone, but not dexamethasone, stimulated EGFR expression in vivo in the aorta as well as in HAoSMC. EGFR degradation was not affected. Aldosterone-induced EGFR expression in HAoSMC was dose dependent and prevented by spironolactone. Furthermore, incubation of HAoSMC with aldosterone led to enhanced EGF-induced ERK1/2 phosphorylation and an EGFR-dependent increase in media fibronectin. EGFR promoter reporter gene assay as well as chromatin immunoprecipitation data indicate that MR interacts with the EGFR promoter. With deletion constructs we gained evidence that this interaction takes place between the hMR and the EGFR promoter regions 316163 (stronger activation site, EC 50 1.0 nM) and 1631 (weaker activation site, EC 50 0.7 nM), which do not comprise canonical glucocorticoid response elements and are not activated by the human glucocorticoid receptor. The interactions require in part the NH 2 -terminal domains of MR. ELISA-based transcription factor DNA binding assay with in vitro synthesized hMR suggest direct binding to region 1631. Our results indicate that aldosterone leads to enhanced EGFR expression via an interaction with the EGFR promoter, which is MR specific and could contribute to the aldosterone-induced increase in fibronectin abundance.
epidermal growth factor receptor; vascular smooth muscle cell
Address for reprint requests and other correspondence: M. Gekle, Physiologisches Institut, Universitaet Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany (e-mail: michael.gekle{at}mail.uni-wuerzburg.de )