Oxidative Stress in Age-Related Macular Degeneration: Nrf2 as Therapeutic Target

The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor-promoting effects.

To estimate the cause-specific prevalence and distribution of blindness and low vision in the United States by age, race/ethnicity, and gender, and to estimate the change in these prevalence figures over the next 20 years. Summary prevalence estimates of blindness (both according to the US definition of < or =6/60 [< or =20/200] best-corrected visual acuity in the better-seeing eye and the World Health Organization standard of < 6/120 [< 20/400]) and low vision (< 6/12 [< 20/40] best-corrected vision in the better-seeing eye) were prepared separately for black, Hispanic, and white persons in 5-year age intervals starting at 40 years. The estimated prevalences were based on recent population-based studies in the United States, Australia, and Europe. These estimates were applied to 2000 US Census data, and to projected US population figures for 2020, to estimate the number of Americans with visual impairment. Cause-specific prevalences of blindness and low vision were also estimated for the different racial/ethnic groups. Based on demographics from the 2000 US Census, an estimated 937 000 (0.78%) Americans older than 40 years were blind (US definition). An additional 2.4 million Americans (1.98%) had low vision. The leading cause of blindness among white persons was age-related macular degeneration (54.4% of the cases), while among black persons, cataract and glaucoma accounted for more than 60% of blindness. Cataract was the leading cause of low vision, responsible for approximately 50% of bilateral vision worse than 6/12 (20/40) among white, black, and Hispanic persons. The number of blind persons in the US is projected to increase by 70% to 1.6 million by 2020, with a similar rise projected for low vision. Blindness or low vision affects approximately 1 in 28 Americans older than 40 years. The specific causes of visual impairment, and especially blindness, vary greatly by race/ethnicity. The prevalence of visual disabilities will increase markedly during the next 20 years, owing largely to the aging of the US population.

The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress.