Diet-induced renal changes in Zucker rats are ameliorated by the superoxide dismutase mimetic TEMPOL.
Diet-induced renal changes in Zucker rats are ameliorated by the superoxide dismutase mimetic TEMPOL.
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DOI：
10.1038/oby.2009.137
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发表时间：
2009-11
期刊：
影响因子：
6.9
通讯作者：
Francis, Joseph
中科院分区：
文献类型：
--
作者：
Ebenezer, Philip J.;Mariappan, Nithya;Elks, Carrie M.;Haque, Masudul;Francis, Joseph
在美国，糖尿病肾病是肾衰竭的主要原因。肥胖Zucker大鼠（OZR; fa/fa）是2型糖尿病和代谢综合征（MetS）以及这些疾病中常见的肾病和肾脏氧化应激的常用模型。杂合子瘦Zucker大鼠（LZRs; fa/+）易患高脂肪饮食（HFD）诱导的肥胖和MetS。本研究旨在探讨超氧化物清除剂4-羟基-2,2,6,6-四甲基哌丁酰氧基（TEMPOL），一种膜透性自由基清除剂，是否可以缓解高脂饮食（类似于典型的“西方”饮食）对OZR和LZR肾脏的影响。饲喂高通量饲料（OZR-HFD和LZR-HFD）或常规饲料（OZR- rd和LZR- rd），并允许其自由饮水或含1 mmol/l TEMPOL的水，为期10周。与OZR-RD动物相比，OZR-HFD动物的总肾皮质活性氧（ROS）生成、血脂、胰岛素、c反应蛋白、血尿素氮（BUN）、肌酐（Cr）和尿白蛋白排泄水平显著高于OZR-RD动物（P < 0.05）；血浆高密度脂蛋白水平显著降低（P < 0.05）。OZR-HFD大鼠肾皮质组织中desmin、肿瘤坏死因子-α (TNF-α)、核因子κB （NFκB）、NAD(P)H氧化酶-1 (NOX-1) mRNA表达水平显著升高；电泳迁移位移法测定的NFκB p65 DNA结合活性在这些动物中也明显更高。在LZR-HFD动物中也发现了同样的趋势。我们的数据表明，TEMPOL可能在治疗早期与MetS相关的肾病方面是有益的。
Diabetic nephropathy is the leading cause of renal failure in the United States. The obese Zucker rat (OZR; fa/fa) is a commonly used model of type 2 diabetes and metabolic syndrome (MetS), and of the nephropathy and renal oxidative stress commonly seen in these disorders. Heterozygous lean Zucker rats (LZRs; fa/+) are susceptible to high-fat diet (HFD)-induced obesity and MetS. The present study was designed to investigate whether superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL), a membrane-permeable radical scavenger, could alleviate the renal effects of MetS in OZR and LZR fed a HFD, which resembles the typical “Western” diet. OZR and LZR were fed a HFD (OZR-HFD and LZR-HFD) or regular diet (OZR-RD and LZR-RD) and allowed free access to drinking water or water containing 1 mmol/l TEMPOL for 10 weeks. When compared to OZR-RD animals, OZR-HFD animals exhibited significantly higher levels of total renal cortical reactive oxygen species (ROS) production, plasma lipids, insulin, C-reactive protein, blood urea nitrogen (BUN), creatinine (Cr), and urinary albumin excretion (P < 0.05); these changes were accompanied by a significant decrease in plasma high-density lipoprotein levels (P < 0.05). The mRNA expression levels of desmin, tumor necrosis factor-α (TNF-α), nuclear factor κB (NFκB), and NAD(P)H oxidase-1 (NOX-1) were significantly higher in the renal cortical tissues of OZR-HFD animals; NFκB p65 DNA binding activity as determined by electrophoretic mobility shift assay was also significantly higher in these animals. The same trends were noted in LZR-HFD animals. Our data demonstrate that TEMPOL may prove beneficial in treating the early stages of the nephropathy often associated with MetS.
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