Angiotensin-(1-7)–Angiotensin-Converting Enzyme 2 Attenuates Reactive Oxygen Species Formation to Angiotensin II Within the Cell Nucleus

The angiotensin (Ang) type 1 receptor (AT1R) is highly expressed on renal nuclei and stimulates reactive oxygen species (ROS). It is not known whether other functional components of the Ang system regulate the nuclear Ang II-AT1R ROS pathway. Therefore, we examined the expression of Ang receptors in nuclei isolated from the kidneys of young adult (1.5 years) and older adult (3.0 to 5.0 years) sheep. Binding studies in renal nuclei revealed the AT2R as the predominant receptor subtype (≈80%) in young sheep, with the Ang-(1-7) (AT7R; Mas protein) and AT1R antagonists competing for the remaining sites. Conversely, in older sheep, the AT1R accounted for ≈85% of nuclear sites, whereas the Ang type 2 receptor and AT7R subtypes comprise ≈20% of remaining sites. Ang II increased nuclear ROS to a greater extent in older (97±22%; n=6) versus young animals (7±2%; P=0.01; n=4), and this was abolished by an AT1R antagonist. The AT7R antagonist D-Ala-Ang-(1-7) increased ROS formation to Ang II by ≈2-fold (174±5% versus 97±22%; P