CYCLOSPORINE INCREASES LOCAL GLOMERULAR SYNTHESIS OF REACTIVE OXYGEN SPECIES IN RATS 1

Background. We report an investigation of the effects of cyclosporine (CsA) on kidney function, the glomerular synthesis of reactive oxygen species, the peroxidation of lipids, and the levels of thromboxane B 2 (TXB2). The effect of the simultaneous administration of the antioxidant vitamin E (Vit E) and CsA in rats was also evaluated. Methods. Adult male Wistar rats were treated for 30 days with CsA (30 mg/kg/day), with Vit E (0.05 mg/ml), with CsA plus Vit E, or with the vehicle used for administration of CsA, namely 12.6% ethanol. Results. CsA induced kidney failure and increased the glomerular synthesis of superoxide anion, H 2O2, malonyldialdehyde, and TXB 2. Vit E minimized the adverse effects of CsA on kidney function and the glomerular synthesis of these compounds. Conclusions. Our results suggest that the acute decrease in glomerular filtration rate induced by CsA might be mediated by the synthesis of reactive oxygen species and subsequent peroxidation of lipids, which increases the levels of TXB 2. Treatment with Vit E prevented these effects, suggesting a possible role for antioxidants in the prevention of CsA nephrotoxicity. The acute nephrotoxicity caused by cyclosporine (CsA*) is manifested by decreases in the renal plasma flow and the glomerular filtration rate (1‐ 6). Several mechanisms have been proposed, including modification of the synthesis of vasoconstrictors (e.g., thromboxane A 2 and endothelin) (7‐9) or of vasodilators (e.g., nitric oxide and prostaglandins) (10, 11). It has been demonstrated that CsA increases the glomerular synthesis and urinary excretion of thromboxane B 2 (TXB2 )( 12‐16). However, the mechanism that is responsible for these phenomena is not yet fully understood. Recent evidence suggests a role for reactive oxygen species in CsA nephrotoxicity (17). Moreover, Wang and Salahudeen (18) have shown that antioxidants can mitigate acute CsA nephrotoxicity. In preliminary experiments with rats that had been treated for 2 weeks with vitamin E (Vit E) before treatment with CsA, we demonstrated that Vit E prevented the acute kidney failure that was otherwise induced by CsA and decreased the glomerular synthesis of TXB 2 (19). However, in clinical practice today, it is sometimes difficult to pretreat patients with antioxidants before they require treatment with CsA. Therefore, we examined the effects of administration of Vit E and CsA in rats. Our goal was to evaluate the effects of CsA on the glomerular synthesis of reactive oxygen species and the peroxidation of lipids in rats and to analyze the possible influence of the antioxidant Vit E on these parameters.