title: Hyperglycemia and liver ischemia reperfusion injury: a role for the advanced glycation endproduct and its receptor pathway.
abstract: Although pretransplant diabetes is a risk factor for mortality post-liver transplant, the underlying mechanism has not been fully defined. In a murine liver partial warm ischemia model, we addressed the question of how diabetes/hyperglycemia impacted tissue inflammatory injuries against ischemia reperfusion (IR), focusing on the advanced glycation endproduct (AGE) and its receptor (RAGE) pathway. Our results showed that hepatocellular injury was exacerbated in streptozotocin-induced diabetic mice against IR, in association with hyper-inflammatory immune activation in livers. Serum levels of AGEs, but not HMGB1, were increased in diabetic mice in response to liver IR. Both RAGE antagonist peptides and small interfering RNA alleviated liver injuries and inhibited inflammatory immune activation against IR in diabetic, but not normal, mice. Kupffer cells (KCs)/macrophages, but not hepatocytes, from diabetic mice expressed significantly higher levels of RAGE, leading to their hyper-inflammatory responsiveness to both TLR ligands and AGEs. In vitro, hyperglycemia increased macrophage RAGE expression and enhanced their TLR responses. Our results demonstrated that activation of the AGE-RAGE signaling pathway in KCs was responsible for hyper-inflammatory immune responses and exacerbated hepatocellular injuries in diabetic/hyperglycemic hosts against liver IR.
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: S
authors.initials: S
authors.lastname: Yue
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: H M
authors.initials: HM
authors.lastname: Zhou
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Liver Surgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: J J
authors.initials: JJ
authors.lastname: Zhu
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: J H
authors.initials: JH
authors.lastname: Rao
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications*; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013311:Streptozocin / Q000494:pharmacology
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D013311:Streptozocin; D000410:Alanine Transaminase
keywords: cytokines/cytokine receptors; diabetes; immune/inflammatory; ischemia reperfusion injury (IRI); liver disease; macrophage/monocyte biology: activation