Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells.
Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells.
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DOI：
10.1038/cddis.2012.40
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发表时间：
2012-04-19
影响因子：
9
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中科院分区：
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缺氧和氧化应激会加速衰老。由于透镜处于缺氧的低血糖环境中，因此患有糖尿病的老化透镜可能会加剧这些应力。本研究旨在检测低氧条件下低糖是否诱导透镜上皮细胞（LEC）的未折叠蛋白反应（UPR），以及UPR是否产生活性氧（ROS）。通过在缺氧条件下在<1.5mM葡萄糖中培养人LEC（HLEC）和大鼠LEC，在1小时内激活UPR。这些条件还诱导Nrf2依赖性抗氧化剂保护性UPR、ROS产生和细胞凋亡。位于前中央区的大鼠晶状体上皮细胞对UPR的敏感性最低，而位于生发区的增殖期晶状体上皮细胞对UPR的敏感性最高。由于皮质透镜纤维细胞在糖尿病发作后从晶状体上皮细胞分化而来，我们认为这些新形成的皮质纤维具有较低水平的Nrf2，然后被氧化导致皮质性白内障。因此，低葡萄糖和氧气条件诱导UPR，ROS的产生，并以正常水平表达Nrf2和Nrf2依赖性抗氧化酶。但这些细胞最终会失去还原型谷胱甘肽（GSH）并诱导细胞凋亡。结果提示低氧低血糖与HLEC功能损害之间存在新的联系。
Aging is enhanced by hypoxia and oxidative stress. As the lens is located in the hypoglycemic environment under hypoxia, aging lens with diabetes might aggravate these stresses. This study was designed to examine whether low glucose under hypoxic conditions induces the unfolded protein response (UPR), and also if the UPR then generates the reactive oxygen species (ROS) in lens epithelial cells (LECs). The UPR was activated within 1 h by culturing the human LECs (HLECs) and rat LECs in <1.5 mM glucose under hypoxic conditions. These conditions also induced the Nrf2-dependent antioxidant-protective UPR, production of ROS, and apoptosis. The rat LECs located in the anterior center region were the least susceptible to the UPR, whereas the proliferating LECs in the germinative zone were the most susceptible. Because the cortical lens fiber cells are differentiated from the LECs after the onset of diabetes, we suggest that these newly formed cortical fibers have lower levels of Nrf2, and are then oxidized resulting in cortical cataracts. Thus, low glucose and oxygen conditions induce the UPR, generation of ROS, and expressed the Nrf2 and Nrf2-dependent antioxidant enzymes at normal levels. But these cells eventually lose reduced glutathione (GSH) and induce apoptosis. The results indicate a new link between hypoglycemia under hypoxia and impairment of HLEC functions.