A constitutively downregulated cytoprotective mechanism in response to oxidative stress and its constant companion, inflammation, may exist in clinical and experimental diabetes. The Nrf2 signaling pathway promotes the expression of a plethora of genes that regulate processes involved in protein stability, proteosome integrity, autophagy, senescence and protection against oxidative stress and inflammation. Nrf2 is held in the cytoplasm as an inactive complex bound to Keap1, which facilitates its ubiquitination. Dissociation of Nrf2 from its repressor Keap1 occurs in response to a stressful insult. Covalent modifications involving phosphorylation or acetylation of the free Nrf2 dictates its nucleocytoplasmic localization and henceforth the transcriptional activity of this pleiotropic protein. Bitar and Al-Mulla recently reported that an enhancement in the GSK-3β-Fyn signaling mechanism in wounds or fibroblasts of type 2 diabetes contributes to the diminution in Nrf2 nuclear accumulation and the concomitant aberration in the expression of Nrf2-dependent phase 2 antioxidant enzymes. This phenomenon was associated with a significant decrease in key fibroblast functions essential for wound healing, including cell migration and contraction. Overall, the authors newly identified defects in the GSK-3β-Fyn-Nrf2 signaling pathway during diabetes that may assist in placing us on the road for an evidence-based therapy of non-healing chronic wounds.
Keywords: Nrf2; diabetes; fibroblasts; oxidative stress; wound healing.