Resveratrol promotes liver cell survival in mice liver-induced ischemia-reperfusion through unfolded protein response: a possible approach in liver transplantation

Abstract

Background Ischemia-reperfusion (I/R) of the liver is a multifactorial condition that happens during transplantation and surgery. The deleterious effects of I/R result from the acute production of reactive oxygen species (ROS), which can trigger immediate tissue damage and induce a series of destructive cellular responses, including apoptosis organ failure and inflammation. The production of ROS in the I/R process can damage the antioxidant system and cause liver damage. Resveratrol has been shown to have antioxidant properties in several investigations. Here, we address the therapeutic effect of resveratrol on I/R-induced liver injury by focusing on unfolded protein response (UPR) signaling pathway. Methods Five minutes before reperfusion, resveratrol was injected into the tail vein of mice. They were ischemic for 1 h and then re-perfused for 3 h before being slaughtered (I/R). The activity of liver enzymes and the expression levels of genes involved in the unfolded protein response pathway were used to measure the hepatic damage. Results Our results revealed that the low dose of resveratrol (0.02 and 0.2 mg/kg) post-ischemic treatment significantly reduced the ALT and AST levels. In addition, compared with the control group, the expression of UPR pathway genes GRP78, PERK, IRE1α, CHOP, and XBP1 was significantly reduced in the resveratrol group. In the mice that received lower doses of resveratrol (0.02 and 0.2 mg/kg), the histopathological changes induced by I/R were significantly improved; however, the highest dose (2 mg/kg) of resveratrol could not significantly protect and solve the I/R damage. Conclusion The findings of this study suggest that hepatic ischemia occurs after liver transplantation and that receiving low-dose resveratrol treatment before reperfusion may promote graft survival through inhibition of UPR arms, especially PERK and IRE1α.

Lipid droplets, autophagy, and ER stress as key (survival) pathways during ischemia‐reperfusion of transplanted grafts

“…IRE1 is an ER transmembrane protein with kinase and RNase activity that dimerizes under ERS (Mohan et al, 2019;Nikawa & Yamashita, 1992). Activated IRE1 inhibits protein transcription in the ER and induces splicing of XBP1 mRNA, resulting in an active form of XBP1 (XBP1-s) (Bertolotti et al, 2000;Korennykh et al, 2009;Uemura et al, 2009). In the nucleus, XBP1-s controls the expression of UPR genes, including chaperones and proteins associated with ERassociated degradation (ERAD) and lipid metabolism (Hetz & Papa, 2018;Korennykh & Walter, 2012).…”

Resveratrol: A Review on the Biological Activity and Applications

“…RSV has been demonstrated to possess antioxidant effects on liver lesions caused by I-R in mice. The results revealed that hepatic ischemia happens after liver transplantation and that the administration of RSV in advance of reperfusion improves graft survival as a consequence of the suppression of protein response signaling pathways, particularly protein kinase R-like ER kinase (PERK) and inositol-requiring enzyme 1alpha (IRE1α) [169].…”

Resveratrol: A Review on the Biological Activity and Applications

“…RSV has been demonstrated to possess antioxidant effects on liver lesion caused by I-R in mice. The results revealed that hepatic ischemia happens after liver transplantation and that the administration of RSV in advance of reperfusion improves graft survival as a consequence of suppression of protein response signaling pathways, particularly protein kinase R-like ER kinase (PERK) and inositol-requiring enzyme 1alpha (IRE1α) [154].…”