In proximal tubular epithelial cells Mrp2 is expressed in apical cell membranes and contributes to the secretion of xenobiotics such as cyclosporine A (CSA). In patients certain MRP2 genotypes are associated with increased susceptibility to drug toxicity and CSA contributes to allograft nephropathy. We tested the hypothesis that kidney-specific deletion of Mrp2 increases CSA-induced kidney graft toxicity through increased oxidative stress. Kidney- specific deletion of Mrp2 was achieved by renal cross transplantation between congenic wild-type and Mrp2-deficient rats followed by removal of both native kidneys. In controls syngenic transplantations were performed. Animals were treated with CSA at 10mg/kg or 30mg/kg for one week (n = 7-8 per group). Renal cortical oxidative stress was assessed by biochemical and gene expression analyses. Renal vascular function was investigated in vivo. CSA dose-dependently increased the renal cortical oxidized glutathione/reduced glutathione (GSSG/GSH) ratio without significant differences between Mrp2- deficient and wild-type grafts. CSA had no effect on xanthine oxidase (XO)-dependent superoxide formation and dose-dependently decreased superoxide formation by NADPH oxidases (NOX). A PCR array of 84 genes showed differential cortical expression of 9 genes coding for enzymes involved in phase I biotransformation and antioxidant defence between placebo and CSA- treated animals. Only one of these genes (glutathione peroxidase 2) showed a differential (increased) expression in Mrp2-deficient vs. wild- type grafts. CSA at 30 mg/kg reduced GFR by 30% in both Mrp2-deficient and wild-type grafts but had no significant effects on renal vascular resistance, endothelium-dependent vasodilation or ₁-adrenoceptor- and AT₁ receptor-mediated vasoconstriction. Renal Mrp2 is not critical for CSA toxicity in rat kidney grafts. Increased renal GSH oxidation in response to CSA may result from increased mitochondrial superoxide formation or accumulation of electrophilic substances other than reactive oxygen species.