Adiponectin prevents islet ischemia–reperfusion injury through the COX2–TNFα–NF-κB-dependent signal transduction pathway in mice

Abstract

Islets are exceptionally susceptible to ischemia–reperfusion injury, an increased incidence of primary graft nonfunctionality, and β-cell death during a transplant procedure. Therefore, islets require protection during the early stages of the transplant procedure. Based on the beneficial vascular and anti-inflammatory activity of adiponectin, we hypothesize that adiponectin protects islet cells against ischemia–reperfusion injury and graft dysfunction after transplantation. To examine the effects of adiponectin on the resistance of islet ischemia–reperfusion injury, we used the islet hypoxia–reoxygenation injury model and performed kidney subcapsular syngeneic islet transplants to assess the islets' vitality and function. Furthermore, we utilized lipopolysaccharide (LPS)-induced or tumor necrosis factor α (TNFα)-induced damage to islet cells to model the inflammation of post-transplant ischemia–reperfusion injury and transplanted islets in adiponectin knockout mice to explore whether the protective action of adiponectin is involved in TNFα production and nuclear transcription factor-κB (NF-κB) activation. Adiponectin suppressed TNFα production and IκB-α phosphorylation; decreased hypoxia–reoxygenation and LPS-induced and TNFα-induced islet apoptosis; and improved islet function in vivo and in vitro. Our results demonstrate that adiponectin protects the islet from injury. We show that islet protection occurs in response to ischemia–reperfusion and is dependent on the suppression of islet production by TNFα through cyclooxygenase 2 and the inhibition of the TNFα-induced NF-κB activation pathways.