Kowluru Renu A, Kowluru Anjan, Mishra Manish, Kumar Binit
Department of Ophthalmology, Wayne State University, Detroit, MI, USA; Department of Anatomy/Cell Biology, Wayne State University, Detroit, MI, USA.
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; John D Dingell VA Medical Center, Detroit, MI, USA.
Prog Retin Eye Res. 2015 Sep;48:40-61. doi: 10.1016/j.preteyeres.2015.05.001. Epub 2015 May 12.
Diabetic retinopathy remains the major cause of blindness among working age adults. Although a number of metabolic abnormalities have been associated with its development, due to complex nature of this multi-factorial disease, a link between any specific abnormality and diabetic retinopathy remains largely speculative. Diabetes increases oxidative stress in the retina and its capillary cells, and overwhelming evidence suggests a bidirectional relationship between oxidative stress and other major metabolic abnormalities implicated in the development of diabetic retinopathy. Due to increased production of cytosolic reactive oxygen species, mitochondrial membranes are damaged and their membrane potentials are impaired, and complex III of the electron transport system is compromised. Suboptimal enzymatic and nonenzymatic antioxidant defense system further aids in the accumulation of free radicals. As the duration of the disease progresses, mitochondrial DNA (mtDNA) is damaged and the DNA repair system is compromised, and due to impaired transcription of mtDNA-encoded proteins, the integrity of the electron transport system is encumbered. Due to decreased mtDNA biogenesis and impaired transcription, superoxide accumulation is further increased, and the vicious cycle of free radicals continues to self-propagate. Diabetic milieu also alters enzymes responsible for DNA and histone modifications, and various genes important for mitochondrial homeostasis, including mitochondrial biosynthesis, damage and antioxidant defense, undergo epigenetic modifications. Although antioxidant administration in animal models has yielded encouraging results in preventing diabetic retinopathy, controlled longitudinal human studies remain to be conducted. Furthermore, the role of epigenetic in mitochondrial homeostasis suggests that regulation of such modifications also has potential to inhibit/retard the development of diabetic retinopathy.
糖尿病视网膜病变仍然是工作年龄成年人失明的主要原因。尽管一些代谢异常与糖尿病视网膜病变的发生有关，但由于这种多因素疾病的复杂性，任何特定异常与糖尿病视网膜病变之间的联系在很大程度上仍属推测。糖尿病会增加视网膜及其毛细血管细胞中的氧化应激，大量证据表明氧化应激与糖尿病视网膜病变发生过程中涉及的其他主要代谢异常之间存在双向关系。由于胞质活性氧生成增加，线粒体膜受损，膜电位受损，电子传递系统的复合物III也受到影响。酶促和非酶促抗氧化防御系统欠佳进一步助长了自由基的积累。随着疾病病程的进展，线粒体DNA（mtDNA）受损，DNA修复系统受到影响，由于mtDNA编码蛋白的转录受损，电子传递系统的完整性受到阻碍。由于mtDNA生物合成减少和转录受损，超氧化物积累进一步增加，自由基的恶性循环持续自我传播。糖尿病环境还会改变负责DNA和组蛋白修饰的酶，以及对线粒体稳态至关重要的各种基因，包括线粒体生物合成、损伤和抗氧化防御，都会发生表观遗传修饰。尽管在动物模型中给予抗氧化剂在预防糖尿病视网膜病变方面取得了令人鼓舞的结果，但仍有待进行对照的纵向人体研究。此外，表观遗传在 mitochondrial homeostasis 中的作用表明，对这种修饰的调控也有可能抑制/延缓糖尿病视网膜病变的发展。 （注：最后一句中的“mitochondrial homeostasis”可能有误，推测原文是“mitochondrial homeostasis”，意为“线粒体稳态” ）
