Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death
Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death
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DOI：
10.2337/diabetes.53.3.726
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发表时间：
2004-03-01
期刊：
影响因子：
7.7
通讯作者：
Russell, JW
中科院分区：
文献类型：
--
作者：
Vincent, AM;Olzmann, JA;Russell, JW
线粒体在大多数导致程序性细胞死亡（PCD）的途径中的中心作用使我们的研究集中在葡萄糖诱导的神经元变性的机制上。据推测，高血糖神经元损伤是线粒体膜超极化和活性氧形成的结果。本研究不仅提供了进一步的证据来支持我们的葡萄糖诱导的PCD模型，而且还证明了解偶联蛋白（UCPs）阻止这一过程的有效能力。通过Western印迹和免疫细胞化学筛选背根神经节（DRG）神经元的UCP表达。通过腺病毒介导的UCP1和UCP3的过表达来评估单个UCPs预防高血糖PCD的能力。有趣的是，UCP3不仅在肌肉中表达，而且在对照条件下在DRG神经元中表达。UCP3表达在糖尿病大鼠高血糖和培养的神经元中迅速下调。UCPs的过表达阻止葡萄糖诱导的瞬时线粒体膜超极化、活性氧形成和PCD诱导。DRG神经元中UCP3的丢失可能是葡萄糖诱导损伤的重要因素。此外，防止UCP3下调或在DRG神经元中再现解偶联反应的能力构成了避免糖尿病并发症如神经病变的有希望的新方法。
The central role of mitochondria in most pathways leading to programmed cell death (PCD) has focused our investigations into the mechanisms of glucose-induced neuronal degeneration. It has been postulated that hyperglycemic neuronal injury results from mitochondria membrane hyperpolarization and reactive oxygen species formation. The present study not only provides further evidence to support our model of glucose-induced PCD but also demonstrates a potent ability for uncoupling proteins (UCPs) to prevent this process. Dorsal root ganglion (DRG) neurons were screened for UCP expression by Western blotting and immunocytochemistry. The abilities of individual UCPs to prevent hyperglycemic PCD were assessed by adenovirus-mediated overexpression of UCP1 and UCP3. Interestingly, UCP3 is expressed not only in muscle, but also in DRG neurons under control conditions. UCP3 expression is rapidly downregulated by hyperglycemia in diabetic rats and by high glucose in cultured neurons. Overexpression of UCPs prevents glucose-induced transient mitochondrial membrane hyperpolarization, reactive oxygen species formation, and induction of PCD. The loss of UCP3 in DRG neurons may represent a significant contributing factor in glucose-induced injury. Furthermore, the ability to prevent UCP3 downregulation or to reproduce the uncoupling response in DRG neurons constitutes promising novel approaches to avert diabetic complications such as neuropathy.