Epidermal growth factor receptor promotes diabetic retinal fibrogenesis via YAP-CCN2-dependent manner

Diabetic retinal fibrogenesis is the main cause of retinal function loss in diabetic retinopathy (DR). In this study, we examined whether epidermal growth factor receptor (EGFR) activity in retinal vascular endothelial cells can stimulate retinal Müller cells (rMCs) and retinal fibrosis in DR. We treated diabetic mice with the EGFR kinase inhibitor erlotinib and analysed the effects on extracellular matrix (ECM) deposition and retinal fibrosis. We also evaluated the roles of conditioned medium from primary cultured retinal vascular endothelial cells (RVECs) in the activation of a human Müller cell line (hMCs). We examined the effect of profibrotic connective tissue growth factor (CCN2) on EGFR-dependent retinal fibrosis as well as the activation of Yes-associated protein (YAP). The EGFR inhibitor erlotinib decreased ECM deposition and diabetic fibrosis. Likewise, conditioned medium from diabetic RVECs increased the activation of hMCs in vitro, indicating a paracrine mechanism. Retinal endothelial-specific gene deletion of CCN2 greatly inhibited rMC activation and ECM deposition in diabetic mice. We proved that YAP regulated CCN2, and gene deletion or pharmacological inhibition of YAP could reduce retinal fibrosis and block rMC activation. Further studies showed that EGFR regulated YAP in diabetic retinas by a RhoA/Rock-dependent mechanism. This study demonstrates that RVECs stimulate rMCs and drive fibrosis via EGFR-dependent paracrine mechanisms. EGFR-YAP-CCN2 signaling may provide a potential treatment for diabetic retinal fibrogenesis.