Enhanced MCP-1 expression during ischemia/reperfusion injury is mediated by oxidative stress and NF-κB

Abstract

Background. Renal ischemia/reperfusion injury is a major cause of acute renal failure in both native kidneys and renal allografts. One important feature of such injury is monocyte/macrophage infiltration into the renal tissue. The infiltration of monocytes/macrophages can be induced by chemotactic factors produced by renal cells. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant protein for monocyte recruitment. The objective of the present study was to investigate mechanisms of elevated MCP-1 expression in rat kidney during ischemia/reperfusion injury. Methods. The left kidney was subjected to one hour of ischemia followed by reperfusion for various time periods. The expression of MCP-1 mRNA was determined by nuclease protection assay and MCP-1 protein was identified by immunohistochemistry. Activation of a nuclear factor-kappa B (NF-κB) was determined by electrophoretic mobility shift assay and the level of lipid peroxides in the kidney was measured. Results. There was a significant increase in MCP-1 expression in the ischemia/reperfusion kidney 2 hours after reperfusion (210% of the control). This increase was accompanied by activation of NF-κB, suggesting that this transcription factor might be involved in the event. The number of monocytes was significantly elevated in the kidney 3 days after ischemia/reperfusion. Pretreatment of rats with NF-κB inhibitors not only prevented NF-κB activation induced by ischemia/reperfusion, but also inhibited MCP-1 mRNA expression. Further analysis revealed that oxidative stress and increased IκB-α phosphorylation might be an underlying mechanism for NF-κB activation and subsequent MCP-1 mRNA expression in the ischemia/reperfusion kidney. Conclusion. The present study clearly demonstrates that enhanced MCP-1 expression in rat kidney during ischemia/reperfusion injury is mediated by NF-κB activation and oxidative stress. Elevated MCP-1 expression might be responsible for increased monocyte infiltration in the injured kidney.