线粒体介导产生的活性氧在血管紧张素Ⅱ诱导的肾脏损害中的作用

Role of mitochondrial reactive oxygen species in angiotensin Ⅱ-induced renal injury

摘要:

目的  利用特异性的线粒体活性氧清除剂mitoTEMPO，探讨线粒体介导产生的活性氧（ROS）在血管紧张素Ⅱ（AngⅡ）诱发的肾脏损害中的作用。方法  通过miniosmotic pump对小鼠皮下灌注AngⅡ复制Ang Ⅱ依赖型高血压模型，而对照组小鼠仅皮下灌注生理盐水。Ang Ⅱ依赖型高血压小鼠分为AngⅡ组和Ang Ⅱ + mitoTEMPO组，分别于皮下注射溶媒和mitoTEMPO。实验处理4周后，分别检测小鼠尾动脉收缩压、尿8-异构前列腺素及24 h白蛋白排泄量、肌酐清除率和肾脏中线粒体所产生ROS含量的变化，并同时对肾脏组织病理学的改变进行分析。结果  与对照组比较，AngⅡ组小鼠血压升高、尿8-异构前列腺素和白蛋白排泄量增加、肌酐清除率下降，肾脏中肾小球硬化指数、肾小管间质损害程度均增加，并伴有线粒体介导产生ROS水平的升高（P <0.05）。除血压外，mitoTEMPO能抑制上述病理性变化，从而减轻Ang Ⅱ所诱发的肾脏损害（P <0.05）。结论  在AngⅡ诱发的高血压过程中，特异性的线粒体活性氧清除剂mitoTEMPO抑制该过程诱发的肾脏损害，并同时伴有肾脏线粒体ROS产生的下降。因此，上述研究结果提示线粒体介导产生的ROS能够促进AngⅡ诱发的肾脏损害。

Abstract:

Objective To clarify the role of mitochondrial reactive oxygen species (ROS) in angiotensin Ⅱ (Ang Ⅱ)-induced renal injury by use of a specific scavenger of mitochondrial ROS, mitoTEMPO. Methods The mouse model of Ang Ⅱ-dependent hypertension was induced with infusion of Ang Ⅱ via subcutaneous miniosmotic pump, and the sham mice were given with normal saline. The Ang Ⅱ-dependent hypertensive mice were divided into control (Ang Ⅱ) group and experimental (Ang Ⅱ + mitoTEMPO) group, which were subcutaneously administered with solvent and mitoTEMPO, respectively. Tail-cuff systolic blood pressure, and urinary excretion of 8-isoprostane and albumin, creatinine clearance, and the levels of mitochondrial ROS in the kidneys were assayed, and pathological changes of renal tissues were analyzed after 4 weeks of treatment. Results Compared with the sham mice, Ang Ⅱ infusion led to increased systolic blood pressure and urinary excretion of 8-isoprostane and albumin, decreased creatinine clearance, and enhanced glomerulosclerosis index and renal tubulointerstitial injury (P < 0.05). The results were accompanied by the enhanced mitochondrial ROS production in the kidneys (P < 0.05). However, the treatment with mitoTEMPO alleviated all the above changes except for blood pressure, leading to renal protection (P < 0.05). Conclusions Treatment with a specific scavenger of mitochondrial ROS, mitoTEMPO, can inhibit renal injury during Ang Ⅱ-dependent hypertension, which is associated with the decreased mitochondrial ROS production in the kidneys. Thus, the results suggest that mitochondrial ROS can promote Ang Ⅱ-induced renal injury.