Angiotensin subtype-1 receptor (AT1R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-α (TNF-α) production. Although angiotensin subtype-2 receptor (AT2R), in general, antagonizes AT1R-stimulated activity, it is not known if AT2R has any anti-inflammatory effects. In this study, we tested the hypothesis that AT2R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNF-α production. Changes in AT2R expression, TNF-α production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT 2R but not AT1R, in response to the AT2R agonist, CGP-42112 (CGP, 100nm), or AT2R antagonist PD-123319 (PD, 1 μm). A 100% increase in AT2R expression in response to stimulation with its agonist CGP was observed. Further, AT2R activation reduced TNF-a production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT2R expression by 76%, increased TNF-α production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT2R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-α production and STAT3 signaling. Restoration of AT2R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes.
ASJC Scopus subject areas
- Cell Biology