title: Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice.
abstract: Hepatic ischemia/reperfusion (I/R) injury associated with liver transplantation and hepatic resection is characterized by hepatocellular damage and a deleterious inflammatory response. In this study, we examined whether receptor for advanced glycation end product (RAGE) activation is linked to mechanisms accentuating inflammation on I/R in a murine model of total hepatic ischemia. Animals treated with soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE, displayed increased survival after total hepatic I/R compared with vehicle treatment. TUNEL assay and histologic analysis revealed that blockade of RAGE was highly protective against hepatocellular death and necrosis on I/R; in parallel, proliferating cell nuclear antigen was enhanced in livers of mice treated with sRAGE. Rapid activation of p38, p44/42, stress-activated protein kinase and c-Jun N-terminal kinase mitogen-activated protein kinases, signal transducer and activator of transcription-3, and nuclear translocation of activator protein-1 was evident at early times on I/R. In the remnants of sRAGE-treated livers, however, activation of each of these signaling and transcription factor pathways was strikingly decreased. sRAGE-treated remnants displayed enhanced activation of nuclear factor kappaB, in parallel with increased transcripts for the proregenerative cytokine, tumor necrosis factor-alpha. In conclusion, these data suggest that RAGE modulates hepatic I/R injury, at least in part by activation of key signaling pathways linked to proinflammatory and cell death-promoting responses. We propose that blockade of this pathway may represent a novel strategy to attenuate injury in hepatic I/R and to facilitate regeneration.
authors.affiliation: Division of Liver Diseases and Transplantation, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.forename: Nikki
authors.initials: N
authors.lastname: Feirt
authors.forename: Michael
authors.initials: M
authors.lastname: Goldstein
authors.forename: James
authors.initials: J
authors.lastname: Guarrera
authors.forename: Nikalesh
authors.initials: N
authors.lastname: Ippagunta
authors.forename: Udeme
authors.initials: U
authors.lastname: Ekong
authors.forename: Hao
authors.initials: H
authors.lastname: Dun
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Wu
authors.initials: W
authors.lastname: Qu
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Jean C
authors.initials: JC
authors.lastname: Emond
mesh_terms: D000818:Animals; D016923:Cell Death; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D006706:Homeostasis; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D015398:Signal Transduction / Q000276:immunology; D015996:Survival Rate; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008024:Ligands; D016328:NF-kappa B; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1