Norrin Treatment Prevents Vascular Permeability and Neural Cell Loss While Preserving Vision in Diabetic Rats

Diabetic retinopathy is one of the leading causes of vision loss worldwide and is characterized by breakdown of the blood-retinal barrier (BRB) and increased retinal vascular permeability. Norrin is required for developmental vascularization, BRB formation, and maintenance. Norrin has recently been shown to restore BRB properties after vascular endothelial growth factor and in diabetic animals. Here, we explored the effect of norrin restoration of the BRB on diabetes-induced visual dysfunction. Retinal norrin protein content was lost as visual acuity and contrast sensitivity decreased in a streptozotocin-induced diabetes rat model. Early norrin intervention prevented diabetes-induced vision loss, as measured by optomotor response, and this preservation of vision was associated with reduced neural cell death, inflammation, and vascular permeability. Further, late norrin intervention prevented any further visual loss while normalizing neural cell death, inflammation, and vascular permeability. In addition, diabetes altered microvessel gene expression patterns, specifically those associated with interferon signaling, which were restored by norrin treatment. Norrin treatment also restored vascular barrier properties induced by ischemia-reperfusion. Together, these results provide strong evidence for targeting the norrin signaling pathway as a potential therapeutic strategy to prevent vision loss in diabetes. ARTICLE HIGHLIGHTS We investigated whether norrin treatment can prevent or reverse diabetes-induced visual dysfunction in rats. Norrin treatment preserved visual acuity and contrast sensitivity, reduced neural cell death, inflammation, and vascular permeability, and restored inflammation-related gene expression patterns in diabetic retinas. Our results support targeting the norrin signaling pathway as a potential therapy for maintaining blood-brain barrier properties and preventing vision loss due to diabetes.