N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation

作者：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^*

来源：FASEB Journal, 2023, 37(4): e22878.

DOI：10.1096/fj.202201664RR

• connective tissue growth factor (CTGF)
• CTF2
• diabetic retinopathy (DR)
• N-cadherin cleavage
• retinal fibrosis
• beta-Catenin

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-beta-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.

• 单位
  南方医科大学; 1; 广东省人民医院; 中山大学