Kowluru Renu A
Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA.
Antioxidants (Basel). 2021 May 15;10(5):783. doi: 10.3390/antiox10050783.
Diabetic retinopathy remains the leading cause of vision loss in working-age adults. The multi-factorial nature of the disease, along with the complex structure of the retina, have hindered in elucidating the exact molecular mechanism(s) of this blinding disease. Oxidative stress appears to play a significant role in its development and experimental models have shown that an increase in cytosolic Reacttive Oxygen Speies (ROS) due to the activation of NADPH oxidase 2 (Nox2), is an early event, which damages the mitochondria, accelerating loss of capillary cells. One of the integral proteins in the assembly of Nox2 holoenzyme, Rac1, is also activated in diabetes, and due to epigenetic modifications its gene transcripts are upregulated. Moreover, addition of hyperlipidemia in a hyperglycemic milieu (type 2 diabetes) further exacerbates Rac1-Nox2-ROS activation, and with time, this accelerates and worsens the mitochondrial damage, ultimately leading to the accelerated capillary cell loss and the development of diabetic retinopathy. Nox2, a multicomponent enzyme, is a good candidate to target for therapeutic interventions, and the inhibitors of Nox2 and Rac1 (and its regulators) are in experimental or clinical trials for other diseases; their possible use to prevent/halt retinopathy will be a welcoming sign for diabetic patients.
糖尿病视网膜病变仍是工作年龄成年人视力丧失的主要原因。该疾病的多因素性质以及视网膜的复杂结构，阻碍了对这种致盲疾病确切分子机制的阐明。氧化应激似乎在其发展中起重要作用，实验模型表明，由于NADPH氧化酶2（Nox2）的激活导致胞质活性氧（ROS）增加是一个早期事件，它会损害线粒体，加速毛细血管细胞的丧失。Nox2全酶组装中的一种整合蛋白Rac1在糖尿病中也被激活，并且由于表观遗传修饰，其基因转录物上调。此外，在高血糖环境（2型糖尿病）中添加高脂血症会进一步加剧Rac1-Nox2-ROS的激活，随着时间的推移，这会加速并加重线粒体损伤，最终导致毛细血管细胞加速丧失和糖尿病视网膜病变的发展。Nox2是一种多组分酶，是治疗干预的良好靶点，Nox2和Rac1（及其调节剂）的抑制剂正在针对其他疾病进行实验或临床试验；它们可能用于预防/阻止视网膜病变对糖尿病患者来说将是一个好消息。
