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 hyperinflammatory 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‐Triggered Sphingosine‐1‐Phosphate and Sphingosine‐1‐Phosphate Receptor 3 Signaling Worsens Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization

“…The roles of S1PR3 in IRI may be organ specific, which is perhaps related to cell‐specific expression of S1PR3 . Previous studies have shown that DM increases susceptibility to IRI and that inflammation is an important factor in diabetes . In this study, we found that the S1P/S1PR3 pathway was activated in the KCs of hyperglycemic mice and that CAY10444 could suppress hepatocellular injury and inflammation after IR in STZ‐treated mice but not in control mice.…”

“…Overwhelming epidemiological and clinical data have demonstrated that patients with DM are more sensitive to IRI . Diabetes and its associated hyperglycemia are involved in a variety of ischemic tissue injuries, including in the lungs, brain, kidney, and liver . The numerous functions of S1P include the regulation of cell death, proliferation, motility, differentiation, and inflammation .…”

Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high‐fat diet‐/streptozotocin‐induced diabetes

“…) and ischaemia/reperfusion injury (Yue et al . ). In the present study, the increase in AGE deposition in the liver of the diabetic animals is the first indication of the participation of AGE‐RAGE pathway in diabetic‐induced liver damage.…”

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

“…Two functional mechanisms downstream of RAGE activation were demonstrated important for the disease pathogenesis, Egr-1-mediated MIP2 expression, and Egr-1-independent TNF-a production and apoptosis. We have found in a liver partial ischemia model that RAGE antagonist peptides or shRNA protected livers from early stage IRI only in hyperglycemic, but not normal, hosts 20 . Although functional roles of CD24/Siglec in liver IRI remain to be determined, CD24 deficient mice suffered significantly higher levels of tissue damage in an acetaminophen (AAP)-induced liver injury model by increasing inflammatory cytokine/chemokine production, indicating its negative regulatory roles in liver innate immune responses.…”