Mitochondrial reactive oxygen species in the pathogenesis of early diabetic nephropathy.
Mitochondrial reactive oxygen species in the pathogenesis of early diabetic nephropathy.
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DOI：
10.1111/jdi.12258
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发表时间：
2015-03
影响因子：
3.2
通讯作者：
Araki E
中科院分区：
文献类型：
--
作者：
Nishikawa T;Brownlee M;Araki E
在过去的40年里，一些看似无关的机制被牵连到导致糖尿病并发症的葡萄糖介导损伤的早期阶段。从2000年开始，一系列的文献表明，这些机制中的每一个都反映了一个单一的高血糖诱导过程：线粒体电子传输链产生过量的超氧阴离子。这一发现导致了这一领域的范式转变1，2.在肾脏，高血糖导致肾小球系膜细胞和近端肾小管细胞中的活性氧物种(ROS)增加。高血糖诱导的超氧化物在糖尿病肾小球损伤中的中心致病作用直接得到了以下观察的支持：作为转基因的超氧化物歧化酶的过度表达可以保护8个月大的糖尿病小鼠，使其免受糖尿病小鼠肾小球系膜体积分数增加、肾小球转化生长因子-b增加、IV型胶原增加和血浆肌酐增加的影响。转基因表达的超氧化物歧化酶(SOD)同样可以预防糖尿病视网膜病变和心肌病变。这一范式在杜根等人最近的一篇论文中受到了挑战。4，认为糖尿病大鼠肾脏内ROS减少而不是增加。作者还报道了糖尿病肾脏中AMP激活的蛋白激酶(AMPK)活性、增殖物激活受体C辅活化子1a(PGC1a)蛋白水平和线粒体密度降低，并提示这反映了AMPK活性下降的前馈循环。
Over the past 40 years, a number of seemingly unrelated mechanisms have been implicated in the early stages of glucose-mediated damage responsible for diabetic complications. Starting in 2000, a series of publications showed that each of these mechanisms reflects a single hyperglycemia-induced process: overproduction of superoxide by the mitochondrial electron transport chain. This discovery created a paradigm shift in the field1, 2.In the kidney, hyperglycemia causes increased reactive oxygen species (ROS) in both glomerular mesangial cells and proximal tubular cells. The central pathogenic role of hyperglycemia-induced superoxide in initating diabetic glomerular injury is directly supported by the observation that overexpression of superoxide dismutase as a transgene protects 8-month-old diabetic mice from developing increased fractional mesangial volume, increased glomerular transforming growth factor-b, increased collagen IV and increased plasma creatinine3. Transgenic expression of superoxide dismutase (SOD) similarly prevents diabetic retinopathy and cardiomyopathy. This paradigm has been challenged in a recent paper by Dugan et al. 4, who claim that in the diabetic kidney, ROS are decreased rather than increased. The authors also report that adenine monophosphate(AMP)-activated protein kinase (AMPK) activity, proliferator-activated receptor c coactivator 1a (PGC1a) protein level and mitochondrial density are decreased in the diabetic kidney, and suggest that these reflect a feed-forward cycle of decreased AMPK activity,
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9.3
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