Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

Abstract

Objective To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. Summary Background Data Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. Methods Wild-type (WT) and Nrf2-deficient mice were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60 min hepatic 70% ischemia followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. Results After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage, impaired GSTm1, NQO1, and GCLc inductions, disturbed redox state, and aggravated TNF-α mRNA expression in comparison to WT livers. 15d-PGJ2 treatment protected the livers of WT mice from I/R injury via increased expressions of GSTm1, NQO1 and GCLc, maintained redox status, and decreased TNF-α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by PPARγ antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. Conclusions Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.

Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury

“…The sensitizing effect of Nrf2 ablation was associated with the loss of I/R-responsive induction of Nrf2 target genes (Fig. 6C), which was consistent with previous reports (25,29). Surprisingly and unexpectedly, we found that female Nrf2 Ϫ/Ϫ mice were protected from I/R injury compared with WT females, as confirmed by histology (Fig.…”

“…Interestingly, like EST ablation, the loss of the Nrf2 effect was also gender-specific because male Nrf2 Ϫ/Ϫ mice showed heightened sensitivity to I/R liver injury, as shown by others (25,29) and by us. The sensitization in male Nrf2 Ϫ/Ϫ mice was believed to be due to the loss of I/R-responsive Nrf2 target gene expression (25,29).…”

“…The sensitization in male Nrf2 Ϫ/Ϫ mice was believed to be due to the loss of I/R-responsive Nrf2 target gene expression (25,29). I/R-responsive Nrf2 target gene expression was similarly abolished in female Nrf2 Ϫ/Ϫ mice, suggesting that the reduced antioxidant gene expression might not account for the sexual dimorphic effect of Nrf2 ablation on I/R injury.…”

15-Deoxy-Δ12,14-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy

“…It can be speculated that the reduction of ROS may be related to the activation effect of 15d-PGJ2 on Nrf2. Kudoh et al demonstrated that 15d-PGJ2 showed no apparent reduction in the levels of aminotransferase and ROS in Nrf2 knock-out mice with I/R injury [29] , and the reduced ROS levels can be observed with fluorescence in the 15d-PGJ2 treatment groups when compared to I/R model groups, as shown in Figure 5C. As a result, the reduction of HIF1α in the nucleus can be observed by Western blot and immunohistochemistry in the 15d-PGJ2 treatment group, as shown in Figure 5B and 5C.…”

“…15-Deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ2), a dehydration product of prostaglandin (PG) D2, is one of the best-studied anti-inflammatory prostaglandins and has been verified to exert antiinflammatory and cell-protective functions in various types of cells and animal models [27,28] . Previous studies have demonstrated the protective effects of 15d-PGJ2 on I/R injury in the brain, myocardium, and kidney, and linked the protective effects to the activation of Nrf2 [29,30] . In the present study, the protective effect of 15d-PGJ2 on hepatic I/R injury has been confirmed, and the effects may rely on a reduction of KC activation and on the activation of the Nrf2 pathway, thereby inhibiting ROS generation, apoptosis, and autophagy.…”