The Nrf2/Keap1/ARE Pathway and Oxidative Stress as a Therapeutic Target in Type II Diabetes Mellitus

Figure 1

The Nrf2/Keap1/ARE pathway in type II diabetes mellitus. (A) Under nonstressed conditions, the Nrf2 transcription factor is covalently bound to cysteine residues on its native repressor Keap1 in the cytoplasm. This results in the constitutive ubiquitination and degradation of Nrf2 in the proteasome and inhibition of the anti-oxidant response. (B) Under conditions of electrophilic or oxidative stress, cysteine residues on Keap1 are modified, resulting in the stabilization and translocation of Nrf2 into the nucleus, where it can bind to the promoter region of the ARE and initiate the transcription of various cytoprotective enzymes which function to promote cellular survival through a variety of mechanisms, including the upregulation of antioxidant function, inflammatory inhibition, and the transport of toxic metabolites. These cellular adaptations have been shown to improve a wide array of tissue damage underlying the pathogenesis and progression of diabetes. (B) There are three major mechanisms of Nrf2 induction by small molecule activators. (I) Upstream kinases such as Akt and Erk phosphorylate Nrf2 at specific sites, favoring its release by Keap1 and nuclear translocation. (II) Modification of Keap1 cysteine residues disrupts the Nrf2-Keap1 complex, favoring dissociation of Nrf2 and subsequent nuclear translocation. (III) Inhibition of Nrf2 ubiquitination by Keap1 and degradation by the proteasome augments Nrf2 availability, thus favoring nuclear translocation of Nrf2. Ub: ubiquitination; P: phosphorylation.