Advanced glycation end products induced the epithelial-mesenchymal transition in retinal pigment epithelial cells via ERK activation

Proliferative diabetic retinopathy (PDR), an end-stage diabetic complication, accounts for blindness and low vision in most diabetic patients. Advanced glycation end products (AGEs) and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells are associated with the development of PDR via multifactorial mechanisms. However, whether AGEs can induce the EMT in RPE cells was previously unknown. In this study, we found that AGEs induced the EMT, accompanied by a decreased expression of the epithelial marker ZO-1, increased the expression of the mesenchymal marker fibronectin, elevated the production of EMT-related cytokines such as vascular endothelial growth factor (VEGF) and interleukin-6, and enhanced cell migration ability. Furthermore, the AGEs-induced EMT could be partly reversed by using an inhibitor of ERK activation, U0126. We also found that AGEs could regulate cell apoptosis and the cell cycle while promoting cell phenotype transformation from a typical cobblestone-like to a fibroblast-like morphology. Collectively, these data suggest that AGEs participate in the pathogenesis of PDR by inducing the EMT in an ERK-dependent pathway. Additional studies investigating the role of AGEs in the EMT may be promising for the prevention and treatment of PDR.