title: Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats.
abstract: 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 N omega-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 O(2)(-) 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 O(2)(-) 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 alpha-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 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 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.
authors.affiliation: 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.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Attia
authors.affiliation: 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.
authors.forename: A Marjan G
authors.initials: AMG
authors.lastname: Verhagen
authors.affiliation: 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.
authors.forename: Erik S G
authors.initials: ESG
authors.lastname: Stroes
authors.affiliation: 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.
authors.forename: Ernst E
authors.initials: EE
authors.lastname: van Faassen
authors.affiliation: 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.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: 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.
authors.forename: Sjef J
authors.initials: SJ
authors.lastname: De Kimpe
authors.affiliation: 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.
authors.forename: Hein A
authors.initials: HA
authors.lastname: Koomans
authors.affiliation: 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.
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
authors.affiliation: 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.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D007511:Ischemia / Q000139:chemically induced / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D007672:Kidney Cortex / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D013599:Systole; D013997:Time Factors; D014664:Vasodilation / Q000502:physiology; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D013481:Superoxides; D014810:Vitamin E; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase