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

Wei Xiang, Longhui Li, Fuyan Hong, Yongcheng Zeng, Jin Zhang, Jinye Xie, Gang Shen, Jinhong Wang, Zhenzhen Fang, Weiwei Qi, Xia Yang, Guoquan Gao, Ti Zhou

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2023 Apr

filter terms:

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. © 2023 Federation of American Societies for Experimental Biology.

Citation

Wei Xiang, Longhui Li, Fuyan Hong, Yongcheng Zeng, Jin Zhang, Jinye Xie, Gang Shen, Jinhong Wang, Zhenzhen Fang, Weiwei Qi, Xia Yang, Guoquan Gao, Ti Zhou. N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2023 Apr;37(4):e22878