rf2 Regulates the Hepatoprotective Effects of Remote Ischemic Conditioning in Hemorrhagic Shock

AIMS: Remote ischemic conditioning (RIC) protects against organ ischemia/reperfusion injury in experimental and clinical settings. We have demonstrated that RIC prevents liver and lung inflammation/injury following hemorrhagic shock/resuscitation (S/R). In the current study, we used a murine model of S/R to investigate the role of Nrf2 in mediating hepatoprotection. RESULTS: The combination of RIC with S/R caused a synergistic rise in Nrf2 and its translocation to the nucleus in the liver. Increased activation of Nrf2 by RIC augmented HO-1 and autophagy and exerted hepatoprotection, concurrent with reductions in S/R-induced TNF-α and IL-6. In Nrf2 KO animals, RIC did not exert hepatoprotection, and failed to upregulate HO-1 and autophagy. Furthermore, resuscitating wildtype animals with blood from donor wildtype animals undergoing RIC was hepatoprotective, but not in Nrf2 KO recipient animals. Interestingly, RIC blood from Nrf2 KO donor animals was also not protective when used to resuscitate wildtype animals, suggesting a role for Nrf2 both in the afferent arm of RIC where protective factors are generated and also in the efferent arm where organ protection is exerted. Finally, RIC plasma prevented oxidant-induced zebrafish mortality, but not in Nrf2a morpholino knockdown fish. INNOVATION: Activation of Nrf2 is an essential mechanism underlying the hepatoprotective effects of RIC. Nrf2 appears to play a role in the afferent limb of RIC protection, as its absence precludes the generation of the protective humoral factors induced by RIC. CONCLUSION: Our studies demonstrate the critical role of Nrf2 in the ability of RIC to prevent organ injury following S/R.