title: Cyclosporine nephrotoxicity: attenuation by an antioxidant-inhibitor of lipid peroxidation in vitro and in vivo.
abstract: The exact mechanisms 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.
authors.affiliation: University of Mississippi Medical Center, Jackson 39216-4505.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: A K
authors.initials: AK
authors.lastname: Salahudeen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000633:toxicity*; D004848:Epithelium / Q000187:drug effects; D005919:Glomerular Filtration Rate; D007674:Kidney Diseases / Q000139:chemically induced*; D007684:Kidney Tubules / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D051381:Rats
chemical_list: D000975:Antioxidants; D008054:Lipid Peroxides; D016572:Cyclosporine