Accumulation of 8-hydroxy-2′-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats
Accumulation of 8-hydroxy-2′-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats
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DOI：
10.2337/diabetes.51.5.1588
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发表时间：
2002-05-01
期刊：
影响因子：
7.7
通讯作者：
Nawata, H
中科院分区：
文献类型：
--
作者：
Kakimoto, M;Inoguchi, T;Nawata, H
氧化应激可能参与糖尿病肾病的发病机制。然而，详细的分子机制仍然不确定。在这里，我们报告了链脲佐菌素诱导的糖尿病大鼠肾脏线粒体DNA（mtDNA）的氧化损伤和积累的mtDNA与4,834-bp的缺失。在糖尿病发病后8周，8-羟基-2'-脱氧鸟苷（8-OHdG），这是一个氧化DNA损伤的标志物，在糖尿病大鼠肾脏的线粒体DNA中的水平显着增加，但在核DNA中没有，表明线粒体DNA的主要损伤。PCR半定量分析显示，糖尿病大鼠肾脏线粒体DNA 4，834 bp缺失频率在8周时明显增加，但在4周时无明显变化。从第8周开始的胰岛素治疗干预使糖尿病大鼠肾脏8-OHdG水平的增加迅速正常化，但并没有逆转mtDNA缺失频率的增加。本研究首次证实糖尿病大鼠肾脏线粒体DNA氧化损伤和随后的线粒体DNA缺失可能是累积的。这可能参与了糖尿病肾病的发病机制。
Oxidative stress may contribute to the pathogenesis of diabetic nephropathy. However, the detailed molecular mechanism remains uncertain. Here, we report oxidative mitochondrial DNA (mtDNA) damage and accumulation of mtDNA with a 4,834-bp deletion in kidney of streptozotocin-induced diabetic rats. At 8 weeks after the onset of diabetes, levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is a marker of oxidative DNA damage, were significantly increased in mtDNA from kidney of diabetic rats but not in nuclear DNA, suggesting the predominant damage of mtDNA. Semi-quantitative analysis using PCR showed that the frequency of 4,834-bp deleted mtDNA was markedly increased in kidney of diabetic rats at 8 weeks, but it did not change at 4 weeks. Intervention by insulin treatment starting at 8 weeks rapidly normalized an increase in renal 8-OHdG levels of diabetic rats, but it did not reverse an increase in the frequency of deleted mtDNA. Our study demonstrated for the first time that oxidative mtDNA damage and subsequent mtDNA deletion may be accumulated in kidney of diabetic rats. This may be Involved in the pathogenesis of diabetic nephropathy.