Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: Prevention by chronic therapy with a peroxynitrite scavenger ebselen
Nephropathy in Zucker diabetic fat rat is associated with oxidative and nitrosative stress: Prevention by chronic therapy with a peroxynitrite scavenger ebselen
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DOI：
10.1097/01.asn.0000135971.88164.2c
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发表时间：
2004-09-01
影响因子：
13.6
通讯作者：
Goligorsky, MS
中科院分区：
文献类型：
--
作者：
Chander, PN;Gealekman, O;Goligorsky, MS
具有代谢综合征和高脂血症的Zucker糖尿病脂肪（ZDF）大鼠发展局灶性和节段性硬化。研究了氧化和亚硝化应激在ZDF肾病中的作用。肾组织学，功能，免疫组织学和氧化和亚硝化应激的生化参数进行了评估，在8和22周龄的ZDF和Zucker瘦（ZL）大鼠和慢性治疗后，与依布硒啉，抗氧化剂和过氧亚硝基清除剂。在8周，ZDF大鼠显示高血糖，无蛋白尿或肾病，但较高水平的二氢生物蝶呤和3-硝基酪氨酸（3-NT）修饰的蛋白质与年龄匹配的ZL大鼠相比。在22周，ZDF大鼠发展局灶性和节段性硬化，蛋白尿，肌酐清除率下降，肾组织谷胱甘肽和四氢生物蝶呤水平进一步升高，二氢生物蝶呤和3-NT-修饰的蛋白质，与年龄匹配的ZL大鼠。肾脂质过氧化产物和3-NT修饰蛋白的免疫组织学表达也增加了22周龄的ZDF，但在ZL大鼠。与未治疗的ZDF大鼠相比，慢性依布硒啉治疗ZDF大鼠恢复了谷胱甘肽和四氢生物蝶呤的肾组织水平;防止了二氢生物蝶呤、脂质过氧化产物和3-NT修饰蛋白的显著蓄积;改善了局灶性和节段性硬化、蛋白尿和肌酐清除率下降，而不影响平均血压、体重和血糖。慢性依布硒啉治疗也改善了血管病变与脂质沉积和肾小管间质瘢痕形成，炎症，并上调α-平滑肌肌动蛋白的表达。这些发现表明，ZDF大鼠发展为肾小球、血管和肾小管间质病理学的进行性肾病。氧化和亚硝化应激早于肾病，这是改善过氧亚硝酸盐清除剂依布硒，因此认为它的原因，而不是后果。
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.