Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.
Department of Forensic Medicine, Medical School of Soochow University, 178 East Ganjiang Road, Suzhou, 215213, China.
Exp Eye Res. 2021 Apr;205:108521. doi: 10.1016/j.exer.2021.108521. Epub 2021 Feb 23.
Diabetic retinopathy (DR), the most common ocular complication resulting from diabetes in working-age adults, causes vision impairment and even blindness because of microvascular damage to the retina. Melatonin is an endogenous neurohormone possessing various biological properties, including the regulation of oxidative stress, inflammation, autophagy, and angiogenesis functions. To evaluate the effects of melatonin on DR, we first investigated the role of melatonin in retinal angiogenesis and inner blood-retina barrier (iBRB) under high glucose conditions in vitro and in vivo. Melatonin administration ameliorated high glucose-induced iBRB disruption, cell proliferation, cell migration, invasion and tube formation, and decreased the expression levels of VEGF, MMP-2, and MMP-9. Furthermore, melatonin treatment increased the level of autophagy but decreased the expression levels of inflammation-related factors under high glucose conditions. To further explore the underlying mechanism, we evaluated human retinal microvascular endothelial cells (HRMECs) via tandem mass tags (TMT)-labeled quantitative proteomics under high-glucose conditions with or without melatonin. Bioinformatics analysis results revealed that the main enrichment pathway of differentially expressed proteins (DEPs) was the Wnt pathway. We found that melatonin inhibited the activation of Wnt/β-catenin pathway following DR. These abovementioned protective effects of melatonin under hyperglycemia were blocked by lithium chloride (LiCl; activator of the Wnt/β-catenin signaling pathway). In summary, melatonin exerts protective effects on experimental DR via inhibiting Wnt/β-catenin pathway by, at least partially, alleviating autophagic dysfunction and inflammatory activation.
糖尿病视网膜病变（DR）是成年工作人群中最常见的糖尿病眼部并发症，由于视网膜微血管损伤，导致视力损害甚至失明。褪黑素是一种内源性神经激素，具有多种生物学特性，包括调节氧化应激、炎症、自噬和血管生成功能。为了评估褪黑素对 DR 的影响，我们首先研究了褪黑素在体外和体内高糖条件下对视网膜血管生成和内血视网膜屏障（iBRB）的作用。褪黑素给药改善了高糖诱导的 iBRB 破坏、细胞增殖、细胞迁移、侵袭和管形成，并降低了 VEGF、MMP-2 和 MMP-9 的表达水平。此外，褪黑素处理在高糖条件下增加了自噬水平，降低了炎症相关因子的表达水平。为了进一步探讨潜在的机制，我们在高糖条件下用人视网膜微血管内皮细胞（HRMECs）进行串联质量标签（TMT）标记定量蛋白质组学评估，同时有或没有褪黑素。生物信息学分析结果表明，差异表达蛋白（DEPs）的主要富集途径是 Wnt 途径。我们发现褪黑素抑制了 DR 后 Wnt/β-catenin 通路的激活。上述褪黑素在高血糖下的保护作用被氯化锂（LiCl；Wnt/β-catenin 信号通路的激活剂）阻断。总之，褪黑素通过抑制 Wnt/β-catenin 通路，至少部分缓解自噬功能障碍和炎症激活，对实验性 DR 发挥保护作用。
