title: A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes.
abstract: Nrf2 regulates the expression and coordinated induction of a battery of antioxidant phase 2 genes that protect cells against the cumulative damaging effects of oxidative stress (OS), a major contributor in the development of chronic diabetic complications. Using cultured dermal fibroblasts from rats with type 2 diabetes (DFs), we investigated the intracellular redox status and the adaptive response to OS, in which Nrf2 plays a central role. Our data confirmed that the generation of superoxide by NADPH oxidase and the mitochondria was enhanced in DFs compared with corresponding controls. This was associated with a decrease in the antioxidant capacity and an increase in the sensitivity of these DFs to hydrogen peroxide-induced necrotic cell death. Nrf2 levels in total cell extracts were diminished, and this abnormality appears to stem from a diabetes-related decrease in Nrf2 protein stability. Endogenous (oligomycin) and exogenous (tert-butylhydroquinone) induction of OS enhanced the nuclear translocation of Nrf2 and increased the mRNA expression of Nrf2-sensitive genes in control but not DFs. The activity of the GSK-3β/Fyn axis was increased markedly in DFs when compared with the corresponding controls. Chemical inhibition of GSK-3β mitigated the diabetes-related suppression of the OS-induced nuclear accumulation of Nrf2 and the transcriptional activation of the genes downstream of Nrf2. Overall, these findings suggest that an augmentation in GSK-3β/Fyn signaling during diabetes contributes to a deficit in both the cellular redox state and the Nrf2-based adaptive response to OS. Moreover, they may also offer a new perspective in the understanding and treatment of nonhealing diabetic wounds.
authors: Department of Pharmacology, Faculty of Medicine, Health Sciences Center, University of Kuwait, Safat, Kuwait. milad.bitar@gmail.com
authors: Milad S
authors: MS
authors: Bitar
authors: Fahd
authors: F
authors: Al-Mulla
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006967:Hypersensitivity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3