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Losartan protects liver against ischaemia/reperfusion injury through PPAR ‐ γ activation and receptor for advanced glycation end‐products down‐regulation
Author(s) -
Koh EunJi,
Yoon SeongJin,
Lee SunMee
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12229
Subject(s) - losartan , chemistry , glycation , receptor , angiotensin ii , reperfusion injury , endocrinology , phosphorylation , p38 mitogen activated protein kinases , pharmacology , mapk/erk pathway , medicine , rage (emotion) , agonist , ischemia , biology , biochemistry , neuroscience
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.