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Am J Physiol Renal Physiol 275: F595-F604, 1998;
0363-6127/98 $5.00
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Vol. 275, Issue 4, F595-F604, October 1998

Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine

Zhi Zhong1, Gavin E. Arteel1,2, Henry D. Connor1, Ming Yin1, Moritz V. Frankenberg1, Robert F. Stachlewitz1, James A. Raleigh2,3, Ronald P. Mason4, and Ronald G. Thurman1,2

1 Departments of Pharmacology and 3 Radiation Oncology, 2 Curriculum in Toxicology, University of North Carolina at Chapel Hill 27599; and 4 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

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 attempt to obtain physical evidence for hypoxia and free radical production in kidney following cyclosporin A. Rats were treated daily with cyclosporin 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 alpha -(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) was injected 3 h after cyclosporin A to trap free radicals. Cyclosporin A doubled serum creatinine and decreased glomerular filtration rates by 65% as expected. Pimonidazole adduct binding in the kidney was increased nearly threefold by cyclosporin A, providing physical evidence for tissue hypoxia. Moreover, cyclosporin A increased 4-POBN/radical adducts nearly sixfold 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 time that cyclosporin A causes hypoxia and increases production of a new free radical species exclusively in the kidney. Therefore, it is concluded that cyclosporin A causes renal injury by mechanisms involving hypoxia-reoxygenation, effects which can be prevented effectively by dietary glycine.

reperfusion; hypoxia marker


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