Nrf2 Deficiency in Müller Cells Exacerbates Pathological Neovascularization in Ischemic Retinopathy

作者：Zhenhua Xu, Lingli Zhou, Jie Wang, Hongkwan Cho, Yingxue Cao, L. P. Shi, S.X. Wu, Yangyiran Xie, Jiang Qian, Elia J. Duh · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2025 · DOI：10.1161/atvbaha.125.323301 · 被引用次数：5 · 研究领域：Retinal Diseases and Treatments、Retinal Development and Disorders、Lysosomal Storage Disorders Research

BACKGROUND: Müller cells are the major retinal glial cell type and pivotal regulators of pathological neovascularization in ischemic retinopathy. There is great interest in identifying factors that govern Müller cells in vascular regulation. Nrf2 (NF-E2–related factor 2) plays a major protective role in regulating oxidative stress and inflammation. Our group previously discovered that both global and neuroretinal Nrf2 deficiency suppress retinal revascularization and promote pathological neovascularization in a mouse model of oxygen-induced retinopathy. Here, we investigate the cell-intrinsic role of Nrf2 in Müller cells on retinal angiogenesis. METHODS: The role of Müller cell Nrf2 in retinal angiogenesis was investigated in cell culture and the mouse oxygen-induced retinopathy model. Human retinal endothelial cells were cocultured with primary Müller cells transfected with Nrf2 small-interference RNA. Müller cell–specific Nrf2 knockout mice were subjected to oxygen-induced retinopathy. RNA-seq analysis of a Müller cell–specific RiboTag transcriptome was conducted in wild-type and Nrf2-deficient Müller cells. RESULTS: Silencing Nrf2 in primary Müller cells increased angiogenic activity in retinal endothelial cells. Müller cell–specific Nrf2 deficiency exacerbated pathological neovascularization in oxygen-induced retinopathy, associated with increased Müller cell gliosis and upregulation of retinal Tnfα (tumor necrosis factor alpha). Müller cell Nrf2 deficiency resulted in dy...