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Vitamin E Alleviates Renal Injury, but Not Hypertension, during Chronic Nitric Oxide Synthase Inhibition in Rats

Diana M. Attia^*, A. Marjan G. Verhagen^*, Erik S. G. Stroes, Ernst E. van Faassen, Hermann-Josef Gröne, Sjef J. De Kimpe, Hein A. Koomans^*, Branko Braam^* and Jaap A. Joles^*

Departments of *Nephrology and Hypertension and Vascular Medicine, University Medical Center, Utrecht, The Netherlands; Department of Cellular and Molecular Pathology, German Cancer Institute, Heidelberg, Germany; and Department of Pharmacology, Pharmacy Faculty, Utrecht, The Netherlands.

Correspondence to Dr. Jaap A. Joles, Department of Nephrology and Hypertension, University Medical Center, Room F03.226, Heidelberglaan 100, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Phone: 31-30-2507329; Fax: 31-30-2543492; E-mail: J.A.Joles{at}med.uu.nl

ABSTRACT. Chronic nitric oxide (NO) synthase inhibition in rats causes hypertension, renal vascular injury, and proteinuria. NO deficiency increases superoxide (O₂^-) activity, but the effects of antioxidant treatment on renal injury have not been studied in this model. Exposure of rats to N-nitro-L-arginine (L-NNA) for 4 d markedly decreased NO-dependent relaxation in aortic rings and increased glomerular and renal interstitial monocyte influx, but renal O₂^- activity was not increased. After 7 d, BP and proteinuria were significantly increased. After 21 d of L-NNA treatment, rats displayed severe hypertension, decreased GFR, marked proteinuria, glomerular ischemia, renal vascular and tubulointerstitial injury, and complete loss of NO-dependent relaxation. Renal O₂^- activity was markedly increased [lucigenin-enhanced 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 oxidase, and diphenyleneiodonium, an inhibitor of flavin-containing enzymes, completely 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 with -tocopherol and there was no effect on hypertension or tubulointerstitial injury, but glomerular ischemia, decreases in GFR, and renal vascular injury were prevented and proteinuria was ameliorated. Renal LEC signals were intermediate between control and L-NNA-alone values (181 ± 84 counts/10 mg). Chronic NO synthase inhibition in rats results in marked increases in renal cortical O₂^- activity, mediated by flavin-dependent oxidases. The absence of early increases in renal O₂^- activity, in the presence of endothelial dysfunction and macrophage influx, indicates that increased renal O₂^- activity is neither attributable to NO deficiency per se nor solely related to macrophage influx. The improvement of glomerular function and amelioration of renal vasculitis and proteinuria with vitamin E cotreatment indicate that oxidants are involved in the pathogenesis of renal injury in this model. However, markedly impaired endothelial function and unabated hypertension persist with vitamin E treatment and seem to be directly attributable to NO deficiency.

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