The Role of High-Mobility Group Box-1 in Renal Ischemia and Reperfusion Injury and the Effect of Ethyl Pyruvate

Abstract

Purpose: High mobility group box-1(HMGB1) was identified as a DNA-binding protein that functions as a cofactor for proper transcriptional regulation in somatic cells. Extracellular HMGB1 acts as a potent proinflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. Ethyl pyruvate (EP), a stable aliphatic ester derived from pyruvic acid, was first described as a pharmacological inhibitor of HMGB1 secretion. We designed this study to identify changes in HMGB1 expression in rat kidney tissues after ischemia reperfusion injury and effects of EP on the expression of HMGB1. Materials and Methods: Sprague-Dawley rats (200-300 g) were subjected to 40 minutes of renal warm ischemia. The animals were divided into 3 groups: sham group without warm ischemia, EP group (EP given before ischemia), and ischemic control group. Kidneys were harvested and serum creatinine and TNF-α measured at 6 hours, 1 day, 3 days, and 5 days after reperfusion. We performed immunohistochemical staining of HMGB1. Results: Serum creatinine and TNF-α level were elevated in the ischemic control group and the EP injection group. In the EP injection group, serum creatinine and TNF-α levels were lower than the ischemic control group. In the 40-minute ischemia-reperfusion model, HMGB1 expression increased at 6 hours after reperfusion and decreased gradually at 1, 3, and 5 days after reperfusion. HMGB1 expression was more distinct at the outer medullary area. intraperitoneal EP injection had no effect on HMGB1 expression. Conclusion: From these results, we deduced that the preventive effect of EP on rat kidney ischemia-reperfusion injury was not due to the decreased expression of HMGB1 but the prevention of HMGB1 release. © 2008 Elsevier Inc. All rights reserved.