Role of Nrf2 in the regulation of diabetic retinopathy

Abstract

Purpose: : Although much is known about pathophysiologic processes contributing to diabetic retinopathy, the role of protective factors has received relatively less attention. Nrf2 is well-known to have a protective role as a regulator of oxidative stress and inflammation. Our group previously found that Nrf2 plays a cytoprotective role retinal ischemia-reperfusion. The objective of this study was to explore the potential role of Nrf2 in diabetic retinopathy (DR).

Methods: : Nrf2 expression was evaluated by immunohistochemistry in post-mortem eyes from individuals with diabetic retinopathy or no diabetes. The STZ model of diabetes was used for investigation of Nrf2 in both wild-type and Nrf2 knockout (Nrf2-/-) mice. Real-time PCR was used to evaluate expression of Nrf2 target genes in DR. Superoxide levels were measured in retinas using the lucigenin assay. Blood-retinal barrier function was assessed in wild-type and knockout mice using [³H] mannitol as a tracer.

Results: : Nrf2 expression in the retina was significantly increased in diabetic retinopathy, with especially prominent expression in Muller glial cells and astrocytes. Nrf2 target genes were induced by diabetes in retinas from wild-type, but not Nrf2 knockout mice, indicating activation of Nrf2 in DR. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared to wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retinal barrier dysfunction in diabetes.

Conclusions: : : These studies indicate that Nrf2 is an important protective factor regulating the progressing of diabetic retinopathy and suggest that treatments augmenting Nrf2 action represent a potential therapeutic strategy for DR.

Keywords: retina • diabetic retinopathy • oxidation/oxidative or free radical damage