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Nephropathy in Zucker Diabetic Fat Rat Is Associated with Oxidative and Nitrosative Stress: Prevention by Chronic Therapy with a Peroxynitrite Scavenger Ebselen

Praveen N. Chander^*, Olga Gealekman, Sergey V. Brodsky, Saban Elitok, Akihiro Tojo, Mark Crabtree^¶, Steven S. Gross^¶ and Michael S. Goligorsky^,

Departments of *Pathology and Medicine, and Renal Research Institute, New York Medical College, Valhalla, New York; Department of Medicine, Tokyo University, Tokyo, Japan; and ^¶Department of Pharmacology, Weill Medical College, Cornell University, New York, New York

Correspondence to Dr. Praveen N. Chander, Department of Pathology, New York Medical College, Valhalla, NY 10595. Phone: 914-594-4172; Fax: 914-594-4161; E-mail: praveen_chander{at}nymc.edu

ABSTRACT. Zucker diabetic fat (ZDF) rats with the metabolic syndrome and hyperlipidemia develop focal and segmental sclerosis. The role of oxidative and nitrosative stress in the nephropathy in ZDF was studied. Renal histology, function, and immunohistologic and biochemical parameters of oxidative and nitrosative stress were evaluated at 8 and 22 wk of age in ZDF and Zucker lean (ZL) rats and after chronic treatment with ebselen, an antioxidant and peroxinitrite scavenger. At 8 wk, ZDF rats showed hyperglycemia, no proteinuria or nephropathy, but higher levels of dihydrobiopterin and 3-nitrotyrosine (3-NT)–modified proteins compared with age-matched ZL rats. At 22 wk, ZDF rats developed focal and segmental sclerosis, proteinuria, decreased creatinine clearance, and renal tissue levels of glutathione and tetrahydrobiopterin with further elevation in dihydrobiopterin and 3-NT–modified proteins, in contrast to age-matched ZL rats. Renal immunohistologic expression of lipid peroxidation products and 3-NT–modified proteins also increased in 22-wk-old ZDF but not in ZL rats. Chronic ebselen treatment of ZDF rats restored renal tissue levels of glutathione and tetrahydrobiopterin; prevented significant accumulation of dihydrobiopterin, lipid peroxidation products, and 3-NT–modified proteins; and ameliorated focal and segmental sclerosis, proteinuria, and fall in creatinine clearance without affecting mean BP, body weight, and blood glucose, compared with the untreated ZDF rats. Chronic ebselen therapy also ameliorated vasculopathy with lipid deposits and tubulointerstitial scarring, inflammation, and upregulated -smooth muscle actin expression. These findings suggest that ZDF rats develop a progressive nephropathy with glomerular, vascular, and tubulointerstitial pathology. Oxidative and nitrosative stress predates the nephropathy, which is improved by peroxinitrite scavenger ebselen, and thus considered its cause and not consequence.

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