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 alpha-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.