Losartan protects liver against ischaemia/reperfusion injury through PPAR ‐ γ activation and receptor for advanced glycation end‐products down‐regulation

Background and Purpose PPAR ‐ γ has been reported to be a protective regulator in ischaemia/reperfusion ( I/R ) injury. The receptor for advanced glycation end‐products ( RAGE ) plays a major role in the innate immune response, and its expression is associated with PPAR ‐ γ activation. Several angiotensin receptor blockers possess partial agonist activities towards PPAR ‐ γ . Therefore, this study investigated the action of losartan, particularly with regard to PPAR ‐ γ activation and RAGE signalling pathways during hepatic I / R . Experimental Approach Mice were subjected to 60 min of ischaemia followed by 6 h of reperfusion. Losartan (0.1, 1, 3 and 10 mg·kg −1 ) was administered 1 h prior to ischaemia and immediately before reperfusion. GW9662 , a PPAR ‐ γ antagonist, was administered 30 min prior to first pretreatment with losartan. Key Results Losartan enhanced the DNA ‐binding activity of PPAR ‐ γ in I/R . Losartan attenuated the increased serum alanine aminotransferase activity, TNF ‐ α and IL ‐6 levels, and nuclear concentrations of NF‐κB in I/R . GW9662 reversed these beneficial effects. Losartan caused a decrease in apoptosis as assessed by TUNEL assay, in release of cytochrome c and in cleavage of caspase‐3, and these effects were abolished by GW9662 administration. Losartan attenuated not only I / R ‐induced RAGE overexpression, but also its downstream early growth response protein‐1‐dependent macrophage inflammatory protein 2 level; phosphorylation of p38, ERK and JNK; and subsequent c‐ J un phosphorylation. GW9662 reversed these effects of losartan administration. Conclusions and Implications Our findings suggest that losartan ameliorates I/R ‐induced liver damage through PPAR ‐ γ activation and down‐regulation of the RAGE signalling pathway.