Oxidative and nitrosative stress in acute renal ischemia.
Generation of reactive oxygen species and nitric oxide in hypoxia-reperfusion injury may form a cytotoxic metabolite, peroxynitrite, which is capable of causing lipid peroxidation and DNA damage. This study was designed to examine the contribution of oxidative and nitrosative stress to the renal damage in ischemic acute renal failure (iARF). iARF was initiated in rats by 45-min renal artery clamping. This resulted in lipid peroxidation, DNA damage, and nitrotyrosine modification confirmed both by Western and immunohistochemical analyses. Three groups of animals were randomly treated with an inhibitor of inducible nitric oxide synthase (NOS), L-N(6)-(1-iminoethyl)lysine (L-Nil), cell-permeable lecithinized superoxide dismutase (SOD), or both. Each treatment resulted in amelioration of renal dysfunction, as well as reduced nitrotyrosine formation, lipid peroxidation, and DNA damage, thus suggesting that peroxynitrite rather than superoxide anion is responsible for lipid peroxidation and DNA damage. Therefore, in a separate series of experiments, a scavenger of peroxynitrite, ebselen, was administered before the reperfusion period. This treatment resulted in a comparable degree of amelioration of iARF. In conclusion, the present study provides the first attempt to elucidate the role of peroxynitrite in initiation of the cascade of lipid peroxidation and DNA damage to ischemic kidneys. The results demonstrate that L-Nil, lecithinized SOD, and ebselen treatments improve renal function due to their suppression of peroxynitrite production or its scavenging, consequently preventing lipid peroxidation and oxidative DNA damage.
Noiri
E
E
Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo 113 - 8655, Japan 910-1193. noiri-tky@umin.ac.jp
Nakao
A
A
Uchida
K
K
Tsukahara
H
H
Ohno
M
M
Fujita
T
T
Brodsky
S
S
Goligorsky
M S
MS
D000818:Animals; D001393:Azoles / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism*; D054833:Isoindoles; D007668:Kidney / Q000098:blood supply*; D015227:Lipid Peroxidation; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D001393:Azoles; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D054833:Isoindoles; C090663:N(6)-(1-iminoethyl)lysine; D009573:Nitrites; D016566:Organoselenium Compounds; D013113:Spin Labels; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; C042986:ebselen; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D008239:Lysine; C001803:tempol