N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation.
Wei XiangLonghui LiFuyan HongYongcheng ZengJin ZhangJinye XieGang ShenJinhong WangZhenzhen FangWeiwei QiXia YangGuoquan GaoTi ZhouPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2023)
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.
Keyphrases
- diabetic retinopathy
- optical coherence tomography
- cell adhesion
- cell migration
- end stage renal disease
- growth factor
- ejection fraction
- chronic kidney disease
- newly diagnosed
- cell proliferation
- peritoneal dialysis
- epithelial mesenchymal transition
- dna binding
- poor prognosis
- prognostic factors
- type diabetes
- transcription factor
- systemic sclerosis
- mass spectrometry
- adipose tissue
- single cell
- optic nerve
- signaling pathway
- binding protein
- vascular endothelial growth factor
- cancer therapy
- wound healing