Oxidative Stress-Related Mechanisms and Antioxidant Therapy in Diabetic Retinopathy

Figure 4

Nrf2-related signal transduction. Oxidative stress activates Nrf2 via dissociating it from its inhibitor Keap1 and translocating to the nucleus, where it binds with the antioxidant-response element (ARE) to regulate transcription of antioxidant genes. At the same time, the expression levels of two other genes are also influenced. On the one hand, Nrf2 fails to bind to the enhancer region of glutamate cysteine ligase catalytic subunit (GCLC), which is an important enzyme in glutathione (GSH) synthesis, thus resulting in the decrease of GSH. On the other hand, hyperglycemia facilities methylation of the Keap1 promoter via methyltransferase enzyme Set7/9 (SetD7), which eases stimulating protein-1 (Sp-1) binding to the promoter, resulting in increased Keap1 expression; therefore, Keap1 combines with Nrf2 and represses Nrf2 in the cytosol. ARE, antioxidant-response element; CH₃, methylation; E, enhancer; GCLC, glutamate cysteine ligase catalytic subunit; GSH, glutathione; P, promoter; SetD7, methyltransferase enzyme Set7/9; Sp-1, stimulating protein-1.