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.

Xiong-Li Yang for the helpful discussion and critical comments on the manuscript. The authors thank the Eye Institute of Henan Academy of Innovations in Medical Science for their assistance in ERG recording. The cartoon schematic diagram was drawn by Figdraw.

This work was supported by the Postdoctoral Research Special Fund of the Third Affiliated Hospital of Zhengzhou University (BSHQDJ2025004), the Joint Construction Project of the Henan Provincial Medical Science and Technology Research Program (LHGJ20240357), the Natural Science Foundation of Henan Province (262300422179), the National Natural Science Foundation of China (32471057; 32271043). Department of Clinical Research and Translational Medicine, Institute of Neuroscience, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China Yun-Tao Qu, Lu-Jia Zhang, Jia-Rui Li, Xiao-Yu Xin, Lu-Ying Han, Xiao-Li Zhang, Bo Lei, Zhongfeng Wang & Yong-Chen Wang Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, China State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China Correspondence to Zhongfeng Wang or Yong-Chen Wang. The authors declare no competing interests.

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