Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats

Chronic nitric oxide (NO) synthase inhibition in rats causes hypertension, renal vascular injury, and proteinuria. NO deficiency increases superoxide (O-2(-)) activity, but the effects of antioxidant treatment on renal injury have not been studied in this model. Exposure of rats to Nw-nitro-L-argini ne (L-NNA) for 4 d markedly decreased NO-dependent relaxation in aortic rin gs and increased glomerular and renal interstitial monocyte influx, but ren al O-2(-) activity was not increased. After 7 d, BP and proteinuria were si gnificantly increased. After 21 d of L-NNA treatment, rats displayed severe hypertension, decreased GFR, marked proteinuria, glomerular ischemia, rena l vascular and tubulointerstitial injury, and complete loss of NO-dependent relaxation. Renal O-2(-) activity was markedly increased [lucigenin-enhanc ed chemiluminescence (LEC), 279 +/- 71 versus 50 +/- 7 counts/10 mg, P < 0. 01; electron paramagnetic resonance spectroscopy, 0.57 +/- 0.05 versus 0.34 +/- 0.04 U/10 mg, P < 0.05]. Apocynin, a specific inhibitor of NADPH oxida se, and diphenyleneiodonium, an inhibitor of flavin-containing enzymes, com pletely inhibited LEC signals in vitro, whereas allopurinol had no effect, indicating that NAD(P)H oxidase plays a major role in superoxide production in the kidney. Endothelial function remained impaired during cotreatment w ith alpha -tocopherol and there was no effect on hypertension or tubulointe rstitial injury, but glomerular ischemia, decreases in GFR, and renal vascu lar injury were prevented and proteinuria was ameliorated. Renal LEC signal s were intermediate between control and L-NNA-alone values (181 +/- 84 coun ts/10 mg). Chronic NO synthase inhibition in rats results in marked increas es in renal cortical O-2(-) activity, mediated by flavin-dependent oxidases . The absence of early increases in renal O-2(-) activity, in the presence of endothelial dysfunction and macrophage influx, indicates that increased renal O-2(-) activity is neither attributable to NO deficiency per se nor s olely related to macrophage influx. The improvement of glomerular function and amelioration of renal vasculitis and proteinuria with vitamin E cotreat ment indicate that oxidants are involved in the pathogenesis of renal injur y in this model. However, markedly impaired endothelial function and unabat ed hypertension persist with vitamin E treatment and seem to be directly at tributable to NO deficiency.