CYCLOSPORINE-A INCREASES HYPOXIA AND FREE-RADICAL PRODUCTION IN RAT KIDNEYS - PREVENTION BY DIETARY GLYCINE

The major side effect of cyclosporin A is severe nephrotoxicity. It is likely that cyclosporin A causes vasoconstriction leading to hypoxia- reperfusion injury; therefore, these experiments were designed to atte mpt to obtain physical evidence for hypoxia and free radical productio n in kidney following cyclosporin A. Rats were treated daily with cycl osporin A (25 mg/kg ig) for 5 days, and pimonidazole, a hypoxia marker , was injected 2 h after the last dose of cyclosporin A. A dose of alp ha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) was injected 3 h a fter cyclosporin A to trap free radicals. Cyclosporin A doubled serum creatinine and decreased glomerular filtration rates by 65% as expecte d. Pimonidazole adduct binding in the kidney was increased nearly thre efold by cyclosporin A, providing physical evidence for tissue hypoxia . Moreover, cyclosporin A increased 4-POBN/radical adducts nearly sixf old in the urine but did not alter levels in the serum. Glycine, which causes vasodilatation and prevents cyclosporin A toxicity, minimized hypoxia and blocked free radical production; however, it did not alter cyclosporin A blood levels. These results demonstrate for the first t ime that cyclosporin A causes hypoxia and increases production of a ne w free radical species exclusively in the kidney. Therefore, it is con cluded that cyclosporin A causes renal injury by mechanisms involving hypoxiareoxygenation, effects which can be prevented effectively by di etary glycine.