RAGE-induced Cytosolic ROS Promote Mitochondrial Superoxide Generation in Diabetes
RAGE-induced Cytosolic ROS Promote Mitochondrial Superoxide Generation in Diabetes
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DOI：
10.1681/asn.2008050514
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发表时间：
2009-04-01
影响因子：
13.6
通讯作者：
Forbes, Josephine M.
中科院分区：
文献类型：
--
作者：
Coughlan, Melinda T.;Thorburn, David R.;Forbes, Josephine M.
受损的线粒体产生过量的超氧化物，这可能介导糖尿病中的组织损伤。我们假设，在糖尿病肾病中，晚期糖基化终产物（AGEs）导致细胞溶质活性氧（ROS）增加，从而促进线粒体超氧化物的产生。在血糖正常的条件下，原代肾细胞暴露于AGEs，用腺病毒载体瞬时过表达AGEs受体（AGEs），以及向健康啮齿动物输注AGEs，均诱导肾细胞溶质氧化应激，导致线粒体通透性转换和线粒体复合物I缺乏。由于缺乏葡萄糖衍生的NADH，这是复合物1的底物，这些变化并没有导致线粒体超氧化物的过量产生;然而，当我们在体外高血糖条件下或糖尿病大鼠中进行这些实验时，我们观察到在复合物I的水平上线粒体超氧化物的显著产生，由NADH的持续供应提供燃料。药理学抑制AGE-β-诱导的线粒体通透性转换在体外废除线粒体超氧化物的生产，我们观察到类似的效果在体内抑制胞浆活性氧的生产与夹竹桃素或降低AGEs与alagelide后。此外，维生素B1缺乏可防止糖尿病诱导的小鼠肾线粒体超氧化物和肾皮质细胞凋亡的增加。综上所述，这些研究表明，AGE-beta诱导的细胞溶质ROS的产生促进线粒体超氧化物的产生在高血糖环境中，提供了进一步的证据，晚期糖基化途径在糖尿病肾病的发展和进展中的作用。
Damaged mitochondria generate an excess of superoxide, which may mediate tissue injury in diabetes. We hypothesized that in diabetic nephropathy, advanced glycation end-products (AGEs) lead to increases in cytosolic reactive oxygen species (ROS), which facilitate the production of mitochondrial superoxide. In normoglycemic conditions, exposure of primary renal cells to AGEs, transient overexpression of the receptor for AGEs (RAGE) with an adenoviral vector, and infusion of AGEs to healthy rodents each induced renal cytosolic oxidative stress, which led to mitochondrial permeability transition and deficiency of mitochondrial complex I. Because of a lack of glucose-derived NADH, which is the substrate for complex 1, these changes did not lead to excess production of mitochondrial superoxide; however, when we performed these experiments in hyperglycemic conditions in vitro or in diabetic rats, we observed significant generation of mitochondrial superoxide at the level of complex I, fueled by a sustained supply of NADH. Pharmacologic inhibition of AGE-RAGE-induced mitochondrial permeability transition in vitro abrogated production of mitochondrial superoxide; we observed a similar effect in vivo after inhibiting cytosolic ROS production with apocynin or lowering AGEs with alagebrium. Furthermore, RAGE deficiency prevented diabetes-induced increases in renal mitochondrial superoxide and renal cortical apoptosis in mice. Taken together, these studies suggest that AGE-RAGE-induced cytosolic ROS production facilitates mitochondrial superoxide production in hyperglycemic environments, providing further evidence of a role for the advanced glycation pathway in the development and progression of diabetic nephropathy.