Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression

Oxidative stress accompanies angiotensin (ANG) II infusion, but the role of ANG type 1 vs. type 2 receptors (AT₁-R and AT₂-R, respectively) is unknown. We infused ANG II subcutaneously in rats for 1 wk. Excretion of 8-isoprostaglandin F_2α (8-Iso) and malonyldialdehyde (MDA) were related to renal cortical mRNA abundance for subunits of NADPH oxidase and superoxide dismutases (SODs) using real-time PCR. Subsets of ANG II-infused rats were given the AT₁-R antagonist candesartan cilexetil (Cand) or the AT₂-R antagonist PD-123,319 (PD). Compared to vehicle (Veh), ANG II increased 8-Iso excretion by 41% (Veh, 5.4 ± 0.8 vs. ANG II, 7.6 ± 0.5 pg/24 h; P < 0.05). This was prevented by Cand (5.6 ± 0.5 pg/24 h; P < 0.05) and increased by PD (15.8 ± 2.0 pg/24 h; P < 0.005). There were similar changes in MDA excretion. Compared to Veh, ANG II significantly (P < 0.005) increased the renal cortical mRNA expression of p22^phox (twofold), Nox-1 (2.6-fold), and Mn-SOD (1.5-fold) and decreased expression of Nox-4 (2.1-fold) and extracellular (EC)-SOD (2.1-fold). Cand prevented all of these changes except for the increase in Mn-SOD. PD accentuated changes in p22^phox and Nox-1 and increased p67^phox. We conclude that ANG II infusion stimulates oxidative stress via AT₁-R, which increases the renal cortical mRNA expression of p22^phox and Nox-1 and reduces abundance of Nox-4 and EC-SOD. This is offset by strong protective effects of AT₂-R, which are accompanied by decreased expression of p22^phox, Nox-1, and p67^phox.