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

Division of Nephrology and Hypertension and Center for Hypertension and Renal Disease Research, Georgetown University, Washington, District of Columbia 20007 Submitted 9 August 2002 ; accepted in final form 18 February 2003 Oxidative stress accompanies angiotensin (ANG) II infusion, but the role of ANG type 1 vs. type 2 receptors (AT 1 -R and AT 2 -R, respectively) is unknown. We infused ANG II subcutaneously in rats for 1 wk. Excretion of 8-isoprostaglandin F 2 (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 AT 1 -R antagonist candesartan cilexetil (Cand) or the AT 2 -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 AT 1 -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 AT 2 -R, which are accompanied by decreased expression of p22 phox , Nox-1, and p67 phox . candesartan; isoprostane; angiotensin receptor blocker; PD-123,319; malonyldialdehyde Address for reprint requests and other correspondence: C. S. Wilcox, Division of Nephrology and Hypertension, Georgetown Univ. Hospital, 3800 Reservoir Rd, N.W., PHC F6003, Washington, DC 20007 (E-mail: wilcoxch{at}georgetown.edu ).