Abstract
122 Chronic rejection in renal allografts is mediated by the interaction between immune and non-immune factors. Ischemia-reperfusion injury can produce direct cellular injury as well potentiate acute and chronic rejection. We wished to study the effects of the lazaroid U-74389G on renal function and renal tubular injury following ischemia-reperfusion and on the expression of genes known to be important in the development of chronic rejection. Male Fisher rats underwent 60 minutes of clamping of the left renal pedicle under anesthesia with simultaneous right nephrectomy. Rats received either citrate vehicle or U-74389G perioperatively (18 mg/kg IV total). Serum creatinine was measured on days 2 and 14. Left kidneys were removed at 2 hrs, 2 days and 14 days and individual sections used for histology and mRNA extraction. Apoptosis was assessed in situ by immunoperoxidase staining using the TUNEL method. Gene expression for MCP-1, RANTES and AIF-1 were measured by semi-quantitative PCR, corrected for actin. Treatment with U-74389G improved renal function as measured by serum creatinine at day 2 (2.0 vs 4.1 mg/dl, p=0.02) and at day 14 (1.3 vs 2.2 mg/dl, p=0.03). Kidneys from untreated animals on day 2 displayed extensive apoptosis of the tubular epithelial cells while animals treated with U-74389G had only the occasional single apoptotic cell amongst mostly normal tubules. Expression of the chemokines MCP-1 and RANTES and the chronic rejection marker AIF-1 was absent in normal kidneys but detectable at levels similar to actin following ischemia-reperfusion injury at 2 hrs and at significantly higher levels by day 14. Pretreatment with U-74389G reduced the expression of these genes to near undetectable levels. The lazaroid U-74389G significantly reduces renal injury in ischemia-reperfusion and prevents the expression of genes with known importance in acute and chronic rejection. This agent has the potential to reduce immune and non-immune injury in renal transplantation, hopefully leading to reduced graft loss from acute and chronic rejection.
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