CYCLOSPORINE NEPHROTOXICITY: ATTENUATION BY AN ANTIOXIDANT-INHIBITOR OF LIPID PEROXIDATION IN VITRO AND IN VIVO

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Abstract
The exact mechanism by which cyclosporine (CsA) causes renal injury is not known. The possibility that reactive oxygen species (ROS) may play a role, since CsA induces renal microsomal lipid peroxidation and reduces glutathione levels, was investigated by examining whether administration of an antioxidant attenuates CsA-induced nephrotoxicity. One of three groups of uninephrectomized rats received vehicles, another CsA 25 mg/kg/day and the third, CsA plus antioxidant lazaroid (U-74389 G) 20 mg/kg/day, for 8 weeks. CsA-induced functional and structural derangements were accompanied by a significant induction of renal cortical lipid peroxidation (thiobarbituric acid reactive substances and conjugated diene). Administration of lazaroid significantly suppressed CsA-induced lipid peroxidation and provided significant functional and structural protection. That lazaroid affords renal functional protection against CsA in the rat was again demonstrable in a crossover study. To examine the relation between CsA nephrotoxicity and lipid peroxidation, cell culture studies were undertaken. CsA induced renal epithelial (LLC-PK1) cell injury (LDH release) as well as lipid peroxidation and degradation (prelabeled 3H arachidonic acid release). Lazaroid prevented CsA-induced cell injury and limited lipid alterations. These new findings—that an antioxidant inhibitor of lipid peroxidation limits CsA induced renal toxicity in vitro and in vivo—suggest a pathogenic role for ROS-mediated lipid peroxidation in CsA-induced renal toxicity. Antioxidant therapy may minimize CsA-induced renal toxicity in humans.

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