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.

Background: 

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 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-minute 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 tumor necrosis factor α mRNA expression in comparison with wild-type livers. 15d-PGJ2 treatment protected the livers of wild-type mice from I/R injury via increased expressions of GSTm1, NQO1, and GCLc; maintained redox status; and decreased tumor necrosis factor α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2^−/− mice and were not annulled by peroxisome proliferator-activated receptor γ 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.

In Brief

The protective role of Nrf2 in hepatic ischemia-reperfusion injury was investigated using wild-type and Nrf2-deficient mice. Oxidative stress and tissue damage after hepatic ischemia-reperfusion were enhanced in Nrf2-deficient mice and suppressed only in wild-type mice treated with an Nrf2 activator before ischemia.