Cyclosporin 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 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.
Zhong
Z
Z
Departments of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA.
Arteel
G E
GE
Connor
H D
HD
Yin
M
M
Frankenberg
M V
MV
Stachlewitz
R F
RF
Raleigh
J A
JA
Mason
R P
RP
Thurman
R G
RG
D000818:Animals; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D005527:Food, Fortified; D005609:Free Radicals / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D005998:Glycine / Q000008:administration & dosage / Q000494:pharmacology*; D000860:Hypoxia; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D008954:Models, Biological; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000517:prevention & control*; D013997:Time Factors; D014661:Vasoconstriction
D005609:Free Radicals; D009593:Nitroimidazoles; C033815:pimonidazole; D016572:Cyclosporine; D003404:Creatinine; D005998:Glycine