Norrin Ameliorates Retinal Ganglion Cell Apoptosis by Normalizing VEGF and PEDF Dysregulation in Diabetic Retinopathy

Diabetic retinopathy is increasingly recognized as a neurovascular disorder rather than a purely vascular disease; however, therapeutic strategies targeting retinal neurodegeneration remain limited. In this study, we investigated the protective effects of norrin against hyperglycemia-induced retinal neurodegeneration and elucidated its underlying molecular mechanisms in diabetic mice. We found that retinal neurodegeneration may precede microvascular leakage in diabetic retinas. Norrin, which is expressed in the inner retina, was significantly downregulated under diabetic conditions. Intravitreal supplementation of norrin markedly attenuated hyperglycemia-induced neurodegenerative processes, leading to retinal ganglion cell (RGC) apoptosis, including oxidative stress, inflammation, and neuropathological alterations such as reactive gliosis, glutamate excitotoxicity, and synaptic dysfunction. Norrin also reduced hyperglycemia-induced microvascular leakage and RGC apoptosis by normalizing vascular endothelial growth factor (VEGF) overexpression and restoring pigment epithelium-derived factor (PEDF) levels. Notably, PEDF upregulated by norrin effectively suppressed neurodegenerative processes induced by hyperglycemia or VEGF, thereby preserving RGC function. These findings identify norrin as a critical modulator of hyperglycemia-induced retinal neurodegeneration through restoration of the VEGF-PEDF balance. Our results highlight norrin as a potential therapeutic target for early neurodegenerative changes in diabetic retinopathy.