Background: Nuclear factor erythroid-derived 2-related factor (Nrf2) is a transcription factor that regulates basal activity and coordinated induction of numerous genes encoding antioxidant and phase II detoxifying enzymes and related proteins and as such plays a critical role in cell defense against oxidative stress. This is evidenced by the observations that severity of ischemic and toxic acute kidney injury (AKI) is markedly increased in Nrf2 Knockout (KO) mice and pre-treatment with Nrf2 activator attenuate AKI in experimental animals. Pancreatic beta cell is well known to be highly vulnerable to oxidative stress.
Aim:To explore the Nrf2-keap1 pathway in islet cells and investigate the effect of pharmacologic activation on isolated islet cell using Nrf 2 KO mice and rats.
Methods: Islet isolation is well known to cause significant oxidative stress.Firstly, Nrf2 knockout mice were used to confirm Nrf2 is critical for the protection from oxidative stress. Secondly, Nrf2 activator was administered to rats prior to isolation to activate Nrf2-keap1 pathway. Isolation results were assessed using FACS, immunofluorescent and western blot.
Results: Islet yield (15.6 ± 4.9 IEQ/g b.w.) and Islet viability (84.5 ± 0.6%) in Nrf2 KO mice were significantly lower than wild-type (24.2 ± 1.9IEQ/g b.w., 93 ± 3.8%, respectively; P<0.05), which indicated that Nrf2 is important for islet survival during isolation. In Nrf2 activator treated rat isolation model, islet yield in treated group (1523 ± 410 IEQ) was significantly higher than control group (1192 ± 223 IEQ, P<0.05). The apoptotic cells in treated group (18.3 ± 2.1%) was significantly lower than control group (23.4 ± 2.1%, P<0.05). The percentage of beta cells in treated group was significantly increased (70.2 ± 4.7% vs. 65.9 ± 4.0%, P<0.05). Increased translocation of Nrf2 to nucleus and enhanced expression of Hemeoxygenase-1 was detected in treated group.
Conclusion:Our results indicate thatNrf2-keap1 pathwayplays a critical role in protecting islets during islet isolation through increasing anti-oxidants. The pharmacological activation of Nrf2-keap1 pathway in islets will be a promising strategy to improve the outcome in clinical islet transplantation.
To cite this abstract in AMA style:Li S, Masuda Y, Hajighasemi-Ossareh M, Le A, Chan J, Foster C, Vaziri N, Ichii H. Protective Effect of Nrf2-keap1 Pathway on Islet Cells Using Islet Isolation Model [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/protective-effect-of-nrf2-keap1-pathway-on-islet-cells-using-islet-isolation-model/. Accessed May 28, 2020.
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