Effect of reactive oxygen species on endothelin-1 production by human mesangial cells
Effect of reactive oxygen species on endothelin-1 production by human mesangial cells
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DOI：
10.1038/ki.1996.25
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发表时间：
1996-01-01
影响因子：
19.6
通讯作者：
Kohan, DE
中科院分区：
文献类型：
--
作者：
Hughes, AK;Stricklett, PK;Kohan, DE
活性氧自由基(ROS)参与了肾缺血再灌注损伤的病理生理过程。肾缺血/再灌流时，内皮素-1(ET-1)大量产生，导致肾血流量和肾小球滤过率下降。观察ROS供体和清除剂对体外培养的人肾小球系膜细胞ET-1蛋白和mRNA水平的影响，以确定ROS是否调节ET-1的产生。与黄嘌呤/黄嘌呤氧化酶、葡萄糖氧化酶或过氧化氢孵育后，ET-1的释放呈剂量依赖性增加。同样，黄嘌呤/黄嘌呤氧化酶或H_2O_2可增强ET-1mRNA水平。相反，ROS清除剂二甲基硫脲(DMTU)、二甲基吡咯啉N-氧化物或吡咯烷二硫代氨基甲酸酯减少了基础ET-1的释放，而DMTU则降低了ET-1mRNA的水平。铁络合剂去铁胺也减少了基础ET-1的释放。超氧化物歧化酶增强黄嘌呤/黄嘌呤氧化酶对ET-1的刺激作用，过氧化氢酶则抑制黄嘌呤/黄嘌呤氧化酶和H_2O_2的作用。ROS的作用与一氧化氮的产生或细胞毒性的变化无关。这些数据表明，外源性或内源性ROS可以增加人系膜细胞产生ET-1。虽然超氧阴离子降低了ET-1的水平，但过氧化氢导致多肽的产生增加。ROS刺激系膜细胞产生ET-1可能参与了肾缺血/再灌注损伤过程中肾小球血流动力学的受损。
Reactive oxygen species (ROS) have been implicated in the pathophysiology of renal ischemia/reperfusion injury. Endothelin-1 (ET-1) is generated in abundance in renal ischemia/reperfusion with resultant decreases in renal blood how and glomerular filtration rate. To determine if ROS regulate ET-1 production, the effect of ROS donors or scavengers on ET-1 protein and mRNA levels in cultured human mesangial cells was examined. Incubation with xanthine/xanthine oxidase, glucose oxidase, or H2O2 caused a dose-dependent rise in ET-1 release. Similarly, xanthine/xanthine oxidase or H2O2 augmented ET-1 mRNA levels. In contrast, the ROS scavengers dimethylthiourea (DMTU), dimethylpyrroline N-oxide, or pyrrolidine dithiocarbamate reduced basal ET-1 release, while DMTU lowered ET-1 mRNA levels. Deferoxamine, an iron chelator, also decreased basal ET-1 release. Superoxide dismutase potentiated the ET-1 stimulatory effect of xanthine/xanthine oxidase, while catalase abrogated the effect of xanthine/xanthine oxidase and H2O2. The effects of ROS were unrelated to changes in nitric oxide production or cytotoxicity. These data indicate that exogenously or endogenously-derived ROS can increase ET-1 production by human mesangial cells. While superoxide anion reduces ET-1 levels, H2O2 leads to enhanced production of the peptide. ROS stimulation of mesangial cell ET-1 production may contribute to impaired glomerular hemodynamics in the setting of renal ischemia/reperfusion injury.