Activity-Dependent Effects of ERK1/2 on Hepatic Ischemia-Reperfusion Injury.

Abstract

Background: Liver transplantation remains the only cure for end-stage liver disease, but ischemia-reperfusion injury (IRI) limits graft availability. Although extracellular signal-regulated kinase (ERK1/2) signaling is involved in cellular responses to IRI, its precise role in hepatic IRI remains unclear. We investigated the role of ERK1/2 in hepatic IRI by modulating its activity using small-molecule chemical inhibitors.

Methods: ERK1/2 activation was monitored at different phases of hepatic IRI using a rat model in which liver ischemia was induced with varying reperfusion times. ERK1/2 activity was modulated in this model by administering different doses of trametinib (MEK1/2 inhibitor) and BCI (DUSP1/6 inhibitor). Liver injury was evaluated through histological assessment, serum markers, and molecular analysis of cell death pathways.

Results: ERK1/2 activity increased early in the reperfusion phase and gradually decreased over 6 hours thereafter. Inhibiting the ERK1/2 activity increase using trametinib (0.3 mg/kg) as well as inhibiting its decreases using BCI (7.5 mg/kg) worsened the liver injury. However, the injury was reduced upon titrating ERK1/2 activity to a moderately increased level by BCI and trametinib coadministration. The reduced liver injury was accompanied by decreased expression of ferroptosis markers.

Conclusions: Our data demonstrate that ERK1/2 activity is required for hepatic cells to tolerate IRI. Our results suggest that modulation of ERK1/2 activity using existing drugs may be a potential therapeutic strategy for mitigating hepatic IRI.