In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of angiotensin II (AngII) induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by tumor necrosis factor-alpha (TNF-α). Systemic blood pressure (SBP) and renal injury responses to chronic infusions of AngII (via implanted mini-pumps) were evaluated for 2 weeks in wild type (WT) and in eNOS knockout mice (KO) co-treated with or without a superoxide (O2-) scavenger, tempol (400 mg/L in the drinking water) or a TNF-α receptor blocker, etanercept (5 mg/kg/day i.p.). In study 1, when AngII was given at a dose of 25 ng/min, it increased mean SBP in WT ( 36± 3 mmHg; n=7) and this effect was attenuated in mice pretreated with tempol ( 24±3 mmHg; n=6). In KO mice (n=9), this dose of AngII resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of AngII (10 ng/min) that increased SBP slightly in WT ( 17 ± 7 mmHg; n=6) but exaggeratedly in KO ( 48 ± 12 mmHg, n=6) associated with severe renal injury. Co-treatment with either tempol (n=6) or etanercept (n=6) ameliorated the hypertensive as well as the renal injury responses in KO compared to WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in AngII.