NADPH oxidases, nuclear factor kappa B, NF-E2-related factor2, and oxidative stress in diabetes

Abstract The link between diabetic vascular complications, and oxidative stress and inflammation is commonly recognized. Nitric oxide (NO) and reactive oxygen species (e.g., O 2 − and H2O2) are signaling molecules governing life processes through oxidative modification of intracellular effectors, including transcription factor nuclear factor kappa B (NF-κB) (activated by O 2 − / H 2 O 2 ), and NF-E2-related factor2 (Nrf2) (activated by O 2 − / H 2 O 2 and NO). NF-κB codes for proinflammatory proteins and its long-term activation causes diabetic complications. Nrf2 codes for antioxidant enzymes, maintains NO synthase transcription and activity, and terminates NF-κB-mediated inflammation. NF-κB/Nrf2 balance determines vascular health. Diabetes results in O 2 − overproduction by some NADPH oxidase isoforms, mitochondria, and others. The O 2 − sources likely activate each other, thus reinforcing their O 2 − -production. The combined O 2 − from these sources mediates NF-κB and Nrf2 activation, but also NO inactivation. Accordingly, NF-κB and Nrf2 are activated in the early stages of diabetes, but over time, likely due to NO inactivation, the activity of Nrf2 decreases and the balance shifts in favor of NF-κB.