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Transcriptional and Translational Regulation of Angiotensin II Type 2 Receptor by Angiotensin II and Growth Factors¹

INSERM-INRA U 418, IFREL, and Université Claude Bernard, Hôpital Debrousse, 69322 Lyon Cedex 05, France

Address all correspondence and requests for reprints to: J. Yuan Li, INSERM-INRA U418, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322 Lyon Cedex 05, France. E-mail: liyuan{at}lyon151.inserm.fr

The regulatory effects of angiotensin-II (AngII) and several growth factors, including insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor ß1 (TGFß1) on the AngII subtype 2 (AT₂) receptor were studied using R3T3 cells, a mouse fibroblast cell line that expresses only AT₂ receptors. AngII increased (in a time- and dose-dependent manner) AT₂ binding sites but had no effects on AT₂ messenger RNA (mRNA) levels. At maximal concentration (10^-7 M) AngII caused a 4-fold increase of AT₂ receptor number. In contrast, IGF-1 increased (3- to 4-fold), whereas bFGF and TGFß1 decreased (by about 90% and 80%, respectively) AT₂ receptor and mRNA levels. Moreover, AngII potentiated the effect of IGF-1 on receptor number, but not on AT₂ mRNA levels, and significantly reduced the inhibitory action of bFGF and TGFß1 on AT₂ binding sites but not on AT₂ mRNA levels. None of these factors modified AT₂ mRNA half-life. The potential effects of these factors on transcription of the AT₂ gene were measured by means of nuclear run-on assays. IGF-1 increased the rate of transcription by about 2.5-fold, whereas bFGF and TGFß1 reduced it by 90 and 80%, respectively. In contrast, AngII did not modify either the basal or IGF-1-stimulated transcription rate. Finally, AngII alone or together with IGF-1, but not IGF-1 alone, increased the attachment of AT₂ mRNA to polysomal fractions. The present findings demonstrate that the main mechanism by which AngII regulates the AT₂ receptor is by increasing the rate of AT₂ mRNA translation, whereas the stimulatory (IGF-1) or inhibitory (bFGF and TGFß1) effects of these growth factors on AT₂ expression are exerted at the transcriptional level.

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