title: Losartan protects liver against ischaemia/reperfusion injury through PPAR-γ activation and receptor for advanced glycation end-products down-regulation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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-Jun phosphorylation. GW9662 reversed these effects of losartan administration.
  
  
  CONCLUSIONS
  Our findings suggest that losartan ameliorates I/R-induced liver damage through PPAR-γ activation and down-regulation of the RAGE signalling pathway.
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors: Eun-Ji
authors: EJ
authors: Koh
authors: Seong-Jin
authors: SJ
authors: Yoon
authors: Sun-Mee
authors: SM
authors: Lee
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D021381:Protein Transport / Q000187:drug effects; D011897:Random Allocation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D016207:Cytokines; D047495:PPAR gamma; D020011:Protective Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019808:Losartan
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