Xiang Wei, Li Longhui, Hong Fuyan, Zeng Yongcheng, Zhang Jin, Xie Jinye, Shen Gang, Wang Jinhong, Fang Zhenzhen, Qi Weiwei, Yang Xia, Gao Guoquan, Zhou Ti
Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
FASEB J. 2023 Apr;37(4):e22878. doi: 10.1096/fj.202201664RR.
Retinal fibrosis is a severe pathological change in the late stage of diabetic retinopathy and is also the leading cause of blindness. We have previously revealed that N-cadherin was significantly increased in type 1 and type 2 diabetic mice retinas and the fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients. However, whether N-cadherin directly induces retinal fibrosis in DR and the related mechanism is unknown. Here, we investigated the pathogenic role of N-cadherin in mediating retinal fibrosis and further explored the relevant therapeutic targets. We found that the level of N-cadherin was significantly increased in PDR patients and STZ-induced diabetic mice and positively correlated with the fibrotic molecules Connective Tissue Growth Factor (CTGF) and fibronectin (FN). Moreover, intravitreal injection of N-cadherin adenovirus significantly increased the expression of FN and CTGF in normal mice retinas. Mechanistically, overexpression of N-cadherin promotes N-cadherin cleavage, and N-cadherin cleavage can further induce translocation of non-p-β-catenin in the nucleus and upregulation of fibrotic molecules. Furthermore, we found a novel N-cadherin cleavage inhibitor, pigment epithelial-derived factor (PEDF), which ameliorated the N-cadherin cleavage and subsequent retinal fibrosis in diabetic mice. Thus, our findings provide novel evidence that elevated N-cadherin level not only acts as a classic EMT maker but also plays a causative role in diabetic retinal fibrosis, and targeting N-cadherin cleavage may provide a strategy to inhibit retinal fibrosis in DR patients.
视网膜纤维化是糖尿病视网膜病变晚期的一种严重病理变化，也是导致失明的主要原因。我们之前已经揭示，在1型和2型糖尿病小鼠视网膜以及增殖性糖尿病视网膜病变（PDR）患者的纤维血管膜中，N-钙黏蛋白显著增加。然而，N-钙黏蛋白是否直接诱导糖尿病视网膜病变中的视网膜纤维化及其相关机制尚不清楚。在此，我们研究了N-钙黏蛋白在介导视网膜纤维化中的致病作用，并进一步探索了相关的治疗靶点。我们发现，PDR患者和链脲佐菌素诱导的糖尿病小鼠中N-钙黏蛋白水平显著升高，且与纤维化分子结缔组织生长因子（CTGF）和纤连蛋白（FN）呈正相关。此外，玻璃体内注射N-钙黏蛋白腺病毒可显著增加正常小鼠视网膜中FN和CTGF的表达。机制上，N-钙黏蛋白的过表达促进其裂解，而N-钙黏蛋白的裂解可进一步诱导非磷酸化β-连环蛋白在细胞核内的转位以及纤维化分子的上调。此外，我们发现了一种新型的N-钙黏蛋白裂解抑制剂，即色素上皮衍生因子（PEDF），它可改善糖尿病小鼠中N-钙黏蛋白的裂解及随后的视网膜纤维化。因此，我们的研究结果提供了新的证据，表明升高的N-钙黏蛋白水平不仅作为经典的上皮-间质转化标志物，而且在糖尿病视网膜纤维化中起致病作用，靶向N-钙黏蛋白裂解可能为抑制糖尿病视网膜病变患者的视网膜纤维化提供一种策略。
