OXYGEN FREE-RADICALS IN ISCHEMIC ACUTE-RENAL-FAILURE IN THE RAT
OXYGEN FREE-RADICALS IN ISCHEMIC ACUTE-RENAL-FAILURE IN THE RAT
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DOI：
10.1172/jci111524
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
FERRIS, TF
中科院分区：
文献类型：
--
作者：
PALLER, MS;HOIDAL, JR;FERRIS, TF
在肾缺血时，ATP被降解为次黄嘌呤。当黄嘌呤氧化酶在分子氧的存在下将次黄嘌呤转化为黄嘌呤时，产生超氧自由基（O2-）。O2-的作用及其还原产物OH .cntdot。探讨其在肾缺血损伤中的介导作用。雄性Sprague-Dawley大鼠行右肾切除术，左肾动脉闭塞60分钟。在肾动脉钳夹前8分钟和解除钳夹前给予氧清除剂超氧化物歧化酶（SOD）。对照大鼠则给予5%葡萄糖。SOD处理大鼠的血浆肌酐较低：在缺血后24、48和72 h分别为1.5、1.0和0.8 mg/dl和2.5、2.5和2.1 mg/dl。缺血24小时后，SOD处理大鼠的胰岛素清除率高于对照组（399 vs. 185 μ l/min）。在缺血加上15分钟再流后测量的肾血流量，SOD处理的大鼠也比对照组大。灌注固定标本组织学判断，SOD处理大鼠肾小管损伤较少。事先用二乙基二硫代氨基甲酸酯孵育使SOD失活的大鼠血浆肌酐值与对照大鼠无差异。OH。cntdot。肾动脉闭塞前给予清除剂二甲基硫脲（DMTU）。DMTU处理大鼠的血浆肌酐低于对照组：在缺血后24、48和72小时分别为1.7、1.7和1.3 mg/dl和3.2、2.2和2.4 mg/dl。SOD和DMTU均未引起正常大鼠肾血流量、尿流量和溶质排泄增加。在缺血前给予黄嘌呤氧化酶抑制剂别嘌呤醇，以防止氧自由基的产生。别嘌呤醇处理大鼠的血浆肌酐较低：在缺血后24、48和72小时为2.7、2.2和1.4 mg/dl，而在缺血后24、48和72小时为3.6、3.5和2.3 mg/dl。过氧化氢酶治疗不能防止肾缺血，可能是因为它的大体积限制了肾小球滤过和进入肾小管腔。研究了肾缺血后超氧化物介导的脂质过氧化作用。60分钟的缺血没有增加肾脏过氧化脂质丙二醛的含量，而缺血加上15分钟的再流导致肾脏过氧化脂质大量增加。在肾缺血前用超氧化物歧化酶（SOD）处理可以阻止回流诱导的肾皮质线粒体脂质过氧化的增加，但对粗皮质匀浆没有作用。氧自由基清除剂SOD、DMTU和抑制自由基生成的别嘌呤醇对缺血后肾功能有保护作用。缺血后再灌注导致脂质过氧化；SOD降低肾缺血再流后皮质线粒体脂质过氧化。缺血肾的氧供应恢复明显导致氧自由基的产生，引起脂质过氧化肾损伤。
During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O2-) is generated. The role of O2- and its reduction product OH .cntdot. in mediating renal injury after ischemia was studied. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O2- scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0 and 0.8 mg/dl vs. 2.5, 2.5 and 2.1 mg/dl at 24, 48 and 72 h postischemia. Some 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 .mu.l/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH .cntdot. scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7 and 1.3 mg/dl vs. 3.2, 2.2 and 2.4 mg/dl at 24, 48 and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2 and 1.4 mg/dl vs. 3.6, 3.5 and 2.3 mg/dl at 24, 48 and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. Sixty minutes of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. The oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. Restoration of O2 supply to ischemic kidney evidently results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.