Evidence for peroxynitrite formation in renal ischemia-reperfusion injury: studies with the inducible nitric oxide synthase inhibitor L-N(6)-(1-Iminoethyl)lysine.
Evidence for peroxynitrite formation in renal ischemia-reperfusion injury: studies with the inducible nitric oxide synthase inhibitor L-N(6)-(1-Iminoethyl)lysine.
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发表时间：
2000-10
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通讯作者：
Lisa M. Walker;Patrick D. Walker;Syed Z. Imam;SYED F. Ali;P. Mayeux
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作者：
Lisa M. Walker;Patrick D. Walker;Syed Z. Imam;SYED F. Ali;P. Mayeux
活性氧被认为参与了缺血再灌注（I-R）损伤。然而，诱导型一氧化氮合酶（iNOS）的诱导和高水平一氧化氮（NO）的产生也有助于这种损伤。NO可以与超氧化物结合形成强氧化剂过氧亚硝酸盐（ONOO(-)）。采用选择性iNOS抑制剂L-N(6)-（1-亚氨基乙基）赖氨酸（L-NIL）在肾I-R损伤大鼠模型中研究NO和ONOO（-）。Sprague-Dawley大鼠双侧肾缺血40分钟，然后给予或不给予L-NIL再灌注6小时。对照动物接受假手术，血浆肌酐值为0.4±0.1 mg/dl。I-R手术显著提高血浆肌酐水平至1.9 +/- 0.3 mg/dl (P < 0.05)，并引起肾皮质坏死。L-NIL （3 mg/kg）可显著降低I-R动物血浆肌酐水平至1.2 +/- 0.10 mg/dl（与I-R相比P < 0.05），并减轻肾小管损伤。通过检测ONOO（-）形成的稳定生物标志物3-硝基酪氨酸-蛋白加合物来评估ONOO（-）的形成。免疫组织化学和高效液相色谱显示，与对照动物相比，I-R动物肾脏的3-硝基酪氨酸蛋白加合物水平升高。l - nil处理大鼠（3 mg/kg）经I-R处理后，3-硝基酪氨酸-蛋白加合物水平下降。这些结果支持了inos产生的NO可能通过ONOO（-）形成介导I-R损伤的假设。
Reactive oxygen species are suggested to participate in ischemia-reperfusion (I-R) injury. However, induction of inducible nitric oxide synthase (iNOS) and production of high levels of nitric oxide (NO) also contribute to this injury. NO can combine with superoxide to form the potent oxidant peroxynitrite (ONOO(-)). NO and ONOO(-) were investigated in a rat model of renal I-R injury using the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine (L-NIL). Sprague-Dawley rats were subjected to 40 min of bilateral renal ischemia followed by 6 h of reperfusion with or without L-NIL administration. Control animals received a sham surgery and had plasma creatinine values of 0.4 +/- 0.1 mg/dl. I-R surgery significantly increased plasma creatinine levels to 1.9 +/- 0.3 mg/dl (P <.05) and caused renal cortical necrosis. L-NIL administration (3 mg/kg) in animals subjected to I-R significantly decreased plasma creatinine levels to 1.2 +/- 0.10 mg/dl (P <.05 compared with I-R) and reduced tubular damage. ONOO(-) formation was evaluated by detecting 3-nitrotyrosine-protein adducts, a stable biomarker of ONOO(-) formation. Immunohistochemistry and HPLC revealed that the kidneys from I-R animals had increased levels of 3-nitrotyrosine-protein adducts compared with control animals. L-NIL-treated rats (3 mg/kg) subjected to I-R showed decreased levels of 3-nitrotyrosine-protein adducts. These results support the hypothesis that iNOS-generated NO mediates damage in I-R injury possibly through ONOO(-) formation.