Protective role of the endothelial isoform of nitric oxide synthase in ANG II-induced inflammatory responses in the kidney.
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 ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-α. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated 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 ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (Δ36 ± 3 mmHg; n = 7), and this effect was attenuated in mice pretreated with tempol (Δ24 ± 3 mmHg; n = 6). In KO mice (n = 9), this dose of ANG II 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 ANG II (10 ng/min) that increased SBP slightly in WT (Δ17 ± 7 mmHg; n = 6) but exaggeratedly in KO (Δ48 ± 12 mmHg, n = 6) associated with severe renal injury. Cotreatment with either tempol (n = 6) or etanercept (n = 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II.
Dept. of Physiology, Hypertension and Renal Center of Excellence, Tulane Univ. Health Sciences Center, New Orleans, LA 70112, USA. majid@tulane.edu.
Curtis
C
Whiting
Alexander
A
Castillo
Mohammed Z
MZ
Haque
Dewan S A
DS
Majid
D043925:Angiogenesis Inducing Agents / Q000633:toxicity; D000804:Angiotensin II / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009393:Nephritis / Q000201:enzymology* / Q000209:etiology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D012259:Ribonuclease, Pancreatic / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D043925:Angiogenesis Inducing Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
angiotensin II; endothelial nitric oxide synthase activity; hypertension; renal injury; superoxide; tumor necrosis factor-α