© 1995 American Heart Association, Inc.
Articles |
Identification of a cis-Acting Glucocorticoid Responsive Element in the Rat Angiotensin II Type 1A Promoter
From the Department of Biochemistry (D.-F.G., S.U., A.I., T.I.), Vanderbilt University, School of Medicine, Nashville, Tenn, and the Research Division (N.N.), The Green Cross Corp, Osaka, Japan.
Correspondence to Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232.
Abstract Enhanced vascular responsiveness to angiotensin II at the AT1 receptor has been considered one of the major contributing factors to vascular hypertrophy and high blood pressure. The transcription of the rat angiotensin II type 1A receptor gene is stimulated by glucocorticoids. To clarify the molecular mechanism for glucocorticoid action in rat vascular smooth muscle cells, we investigated the effects of dexamethasone on the promoter activity of the angiotensin II type 1A receptor by using promoter/luciferase reporter gene constructs and heterologous context constructs (containing the thymidine kinase promoter) in transfected vascular smooth muscle cells (<12 passages). There are three putative glucocorticoid responsive elements (GREs) in the promoter. However, only one GRE was found to respond to dexamethasone (1 µmol/L) and was located at positions -756 to -770 bp upstream from the transcription initiation site. When compared with the consensus sequence of GRE, 9 of 12 bases were identical. RU38486, a glucocorticoid antagonist, completely blocked the induction by dexamethasone, suggesting that the GRE was functional through a specific glucocorticoid receptor. The response to dexamethasone was lost in vascular smooth muscle cells at higher passage numbers (>8 passages) but was restored when the cells were transfected with a glucocorticoid-receptor expression construct. This finding provided additional support that the response to dexamethasone was mediated by the glucocorticoid receptor. The gel mobility supershift assay showed that the GRE binds in vitro–translated rat glucocorticoid receptors in a specific manner. Compared with the angiotensin II type 1A receptor promoter, no effect by dexamethasone was observed in vascular smooth muscle cells transfected with the angiotensin II type 1B receptor promoter/luciferase reporter gene constructs. We conclude from these experiments that the dexamethasone-induced increase in the transcription of the angiotensin II type 1A receptor gene occurred through the binding of GRE to the glucocorticoid-specific receptor.
Key Words: angiotensin II • glucocorticoid responsive element • luciferase • dexamethasone • type 1A receptor
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