Periyasamy Palsamy, Shinohara Toshimichi
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Prog Retin Eye Res. 2017 Sep;60:1-19. doi: 10.1016/j.preteyeres.2017.08.003. Epub 2017 Aug 31.
Age-related cataracts are closely associated with lens chronological aging, oxidation, calcium imbalance, hydration and crystallin modifications. Accumulating evidence indicates that misfolded proteins are generated in the endoplasmic reticulum (ER) by most cataractogenic stresses. To eliminate misfolded proteins from cells before they can induce senescence, the cells activate a clean-up machinery called the ER stress/unfolded protein response (UPR). The UPR also activates the nuclear factor-erythroid-2-related factor 2 (Nrf2), a central transcriptional factor for cytoprotection against stress. Nrf2 activates nearly 600 cytoprotective target genes. However, if ER stress reaches critically high levels, the UPR activates destructive outputs to trigger programmed cell death. The UPR activates mobilization of ER-Ca to the cytoplasm and results in activation of Ca-dependent proteases to cleave various enzymes and proteins which cause the loss of normal lens function. The UPR also enhances the overproduction of reactive oxygen species (ROS), which damage lens constituents and induce failure of the Nrf2 dependent cytoprotection. Kelch-like ECH-associated protein 1 (Keap1) is an oxygen sensor protein and regulates the levels of Nrf2 by the proteasomal degradation. A significant loss of DNA methylation in diabetic cataracts was found in the Keap1 promoter, which overexpresses the Keap1 protein. Overexpressed Keap1 significantly decreases the levels of Nrf2. Lower levels of Nrf2 induces loss of the redox balance toward to oxidative stress thereby leading to failure of lens cytoprotection. Here, this review summarizes the overall view of ER stress, increases in Ca levels, protein cleavage, and loss of the well-established stress protection in somatic lens cells.
年龄相关性白内障与晶状体的自然老化、氧化、钙失衡、水合作用及晶状体蛋白修饰密切相关。越来越多的证据表明，大多数致白内障应激在内质网（ER）中产生错误折叠的蛋白质。为了在错误折叠的蛋白质诱导细胞衰老之前将其从细胞中清除，细胞会激活一种名为内质网应激/未折叠蛋白反应（UPR）的清理机制。UPR还会激活核因子红细胞2相关因子2（Nrf2），这是一种对抗应激的细胞保护核心转录因子。Nrf2可激活近600个细胞保护靶基因。然而，如果内质网应激达到极高水平，UPR会激活破坏性信号以触发程序性细胞死亡。UPR会激活内质网钙向细胞质的动员，并导致钙依赖性蛋白酶的激活，从而切割各种酶和蛋白质，导致晶状体正常功能丧失。UPR还会增强活性氧（ROS）的过量产生，ROS会损害晶状体成分并导致Nrf2依赖性细胞保护功能失效。 Kelch样ECH相关蛋白1（Keap1）是一种氧感应蛋白，通过蛋白酶体降解调节Nrf2的水平。在糖尿病性白内障中，发现Keap1启动子的DNA甲基化显著缺失，这会导致Keap1蛋白过度表达。过度表达的Keap1会显著降低Nrf2的水平。较低水平的Nrf2会导致氧化还原平衡向氧化应激方向失调，从而导致晶状体细胞保护功能失效。在此，本综述总结了内质网应激、钙水平升高、蛋白质切割以及晶状体体细胞中既定应激保护功能丧失的总体情况。
