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

Am J Physiol. 1998 Oct;275(4):F595-604. doi: 10.1152/ajprenal.1998.275.4.F595.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Creatinine / blood
  • Cyclosporine / antagonists & inhibitors
  • Cyclosporine / blood
  • Cyclosporine / toxicity*
  • Food, Fortified
  • Free Radicals / metabolism
  • Glomerular Filtration Rate / drug effects*
  • Glycine / administration & dosage
  • Glycine / pharmacology*
  • Hypoxia
  • Kidney / drug effects*
  • Kidney / pathology
  • Kidney / physiology
  • Male
  • Models, Biological
  • Nitroimidazoles / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Renal Circulation
  • Reperfusion Injury / prevention & control*
  • Time Factors
  • Vasoconstriction


  • Free Radicals
  • Nitroimidazoles
  • pimonidazole
  • Cyclosporine
  • Creatinine
  • Glycine