Cyclosporin a increases hypoxia and free radical production in the
rat kidney: prevention by dietary glycine1.
Zhong, Zhi, Gavin E. Arteel, Henry D. Connor, Ming Yin, Moritz V.
Frankenberg, Robert, F. Stachlewitz, James A. Raleigh, Ronald P.
Mason and Ronald G. Thurman,.
2Depts. of Pharmacology and 4Radiation Oncology, 3Curriculum in
Toxicology, Univ. of North Carolina at Chapel Hill, NC 27599 and
5Lab. Of Pharmacology and Chemistry, NIEHS, RTP, NC 27709
APStracts 5:0133F, 1998.
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, p.o.) for 5 days, and pimonidazole, a
hypoxia marker, was injected 2 hours after the last dose of
cyclosporin A. POBN ((-(4-pyridyl 1-oxide)-N-tert-butylnitrone) was
injected 3 hours 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 3-fold by cyclosporin A, providing
physical evidence for tissue hypoxia. Moreover, cyclosporin A
increased POBN/radical adducts nearly 6-fold 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.
Received 1 October 1997; accepted in final form 30 July 1998.
APS Manuscript Number F318-7.
Article publication pending Am. J. Physiol. (Renal Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 21 September 1998