The influence of changes in expression of redox-sensitive genes on the development of retinopathy in rats.

Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2). AhR-dependent oxidative stress can be attenuated by activation of Nrf2, and defects in the Nrf2 signaling pathway can increase sensitivity of the cell to oxidative stress. Our aim was to determine the role of the pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems in the pathogenesis of AMD using rats of OXYS strain and of OXYSb substrain with signs of AMD-like retinopathy of varying severity. We compared the retinal levels of mRNA expression of Nrf2- and AhR-dependent redox-sensitive systems between 1-, 3-, and 12- month-old senescence-accelerated OXYS rats (have been shown to be a valid experimental model of AMD) and the rat substrain OXYSb, which shows low morbidity of AMD. We uncovered interstrain differences in the expression of Nrf2 and Nrf2-dependent genes (glutathione S-reductase [Gsr] and heme oxygenase 1 [Hmox1]), in the expression of AhR-dependent genes (cytochrome P450 1A2 [Cyp1a2] and cytochrome P450 1B1 [Cyp1b1]), and in the NADPH-quinone oxidoreductase (Nqo1) expression, which is controlled by both AhR and Nrf2. Binding of AhR and Nrf2 proteins to the regulatory regions of AhR and Nrf2 genes, respectively, was detected by chromatin immunoprecipitation in the retina of 1-, 3-, and 12-month-old OXYS, OXYSb, and Wistar (control) rats. We compared the strength of DNA-protein interactions of AhR and Nrf2 with regulatory sequences and found that the level of autoupregulation of the AhR gene was higher in the retina of 1-month-old OXYSb rats in comparison with OXYS rats. An imbalance between pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems may play a crucial role in the onset and/or progression of AMD.