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

Author:

Xiang Wei12,Li Longhui3,Hong Fuyan1,Zeng Yongcheng1,Zhang Jin1,Xie Jinye1,Shen Gang1,Wang Jinhong1,Fang Zhenzhen1,Qi Weiwei14,Yang Xia14,Gao Guoquan15,Zhou Ti167ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine Sun Yat‐sen University Guangzhou China

2. Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou China

3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center Sun Yat‐sen University Guangzhou China

4. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou China

5. Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products Sun Yat‐Sen University Guangzhou China

6. Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine Sun Yat‐sen University Guangzhou China

7. China Key Laboratory of Tropical Disease Control (Sun Yat‐sen University) Ministry of Education Guangzhou China

Abstract

AbstractRetinal 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.

Funder

China Postdoctoral Science Foundation

Fundamental Research Funds for the Central Universities

National Natural Science Foundation of China

Publisher

Wiley

Subject

Genetics,Molecular Biology,Biochemistry,Biotechnology

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