Hyperglycemia and liver ischemia reperfusion injury: A role for the advanced glycation endproduct and its receptor pathway

S. Yue, H. M. Zhou, J. J. Zhu, J. H. Rao, R. W. Busuttil, J. W. Kupiec-Weglinski, L. Lu, Y. Zhai

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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. Hyperglycemia enhances liver inflammatory tissue injury against ischemia-reperfusion by activating the advanced glycation end product and its receptor pathway.

Original languageEnglish (US)
Pages (from-to)2877-2887
Number of pages11
JournalAmerican Journal of Transplantation
Issue number11
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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