Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes.

ABSTRACT

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-)physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed "AT2R binding protein" (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease. In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism. Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP.