Nrf2 Deficiency in Müller Cells Exacerbates Pathological Neovascularization in Ischemic Retinopathy.

Area of Science:

• Ophthalmology
• Neuroscience
• Molecular Biology

Background:

• Müller cells are key regulators of neovascularization in ischemic retinopathy.
• Nuclear factor erythroid 2-related factor 2 (Nrf2) has protective roles in oxidative stress and inflammation.
• Previous studies showed global Nrf2 deficiency impairs retinal revascularization.

Purpose of the Study:

• To investigate the cell-intrinsic role of Nrf2 in Müller cells regarding retinal angiogenesis.
• To understand how Nrf2 in Müller cells impacts pathological neovascularization in ischemic retinopathy.

Main Methods:

• Co-culture of human retinal endothelial cells with Nrf2-silenced Müller cells.
• Oxygen-induced retinopathy model in Müller cell-specific Nrf2 knockout mice.
• RNA-sequencing of Müller cell transcriptomes from wild-type and Nrf2-deficient mice.

Main Results:

• Nrf2 silencing in Müller cells enhanced endothelial cell angiogenic activity.
• Müller cell-specific Nrf2 deficiency worsened pathological neovascularization and increased Tnfα.
• Nrf2 deficiency upregulated Lcn2 and Fgf2, promoting angiogenesis; Lcn2 blockade reduced neovascularization.

Conclusions:

• Nrf2 in Müller cells is crucial for regulating retinal angiogenesis and inflammation in ischemic retinopathy.
• Nrf2 controls Müller cell gene expression, including LCN2, a novel angiogenesis regulator.
• Pharmacological Nrf2 activation presents a potential therapeutic strategy for ischemic retinopathy.