Microglial PGRN downregulation contributes to phagocytosis-mediated retinal microvascular endothelial cell damage in early experimental diabetes

Diabetic retinopathy (DR), a major cause of vision loss, involves retinal microvascular dysfunction. While microglial phagocytosis of endothelial cells has been reported to contribute to diabetic retinal damage, the endogenous mechanisms driving microglial hyperphagocytosis in early DR remain unclear. Here we investigated the interplay between retinal microglia and endothelial cells in early diabetic mice mediated by progranulin (PGRN). PGRN expression in microglia was decreased, accompanied by microglial proliferation, morphological changes, and reduced tight junction proteins. Intravitreal injection of PGRN prevented microglia from engulfing endothelial cells, reversed the reduction of tight junction proteins and the increased number of acellular capillaries. We identified that EphA2/PI3K/Akt/ApoE signaling mediated the suppression of PGRN on microglial phagocytic function in vitro. Importantly, blocking EphA2 prevented the protective effects of PGRN on the vascular dysfunction, and inhibiting PI3K/Akt signaling mimicked the PGRN effects. Moreover, PGRN alleviated visual damage in early diabetic mice. Taken together, our study provides a promising therapeutic target for DR at the early stage of diabetes and offers insight into the interaction between retinal microglia and endothelial cells.