Induction of antioxidant enzymes in murine podocytes precedes injury by puromycin aminonucleoside
Induction of antioxidant enzymes in murine podocytes precedes injury by puromycin aminonucleoside
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DOI：
10.1111/j.1523-1755.2004.00962.x
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发表时间：
2004-11-01
影响因子：
19.6
通讯作者：
Smoyer, WE
中科院分区：
文献类型：
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作者：
Vega-Warner, V;Ransom, RF;Smoyer, WE
背景活性氧（ROS）的产生和抗氧化防御机制之间的不平衡已被认为在肾病综合征足细胞损伤中发挥重要作用。实验性肾病综合征（NS）是由嘌呤霉素氨基糖苷（PAN）诱导的大鼠肾病综合征模型，抗氧化酶（AOE）预处理可在很大程度上预防肾病综合征的发生，提示ROS可能介导足细胞损伤。为了验证PAN诱导的足细胞损伤部分受足细胞抗氧化防御调节的假设，我们使用我们最近报道的PAN诱导的足细胞损伤的体外模型分析了足细胞中AOE活性、脂质过氧化产物和相对ROS水平。PAN治疗诱导早期增加足细胞过氧化氢和超氧化物，后来增加脂质过氧化产物。与基线活性相比，PAN还引起主要细胞AOE活性的显着变化（与时间匹配的对照相比，过氧化氢酶最大增加151%，超氧化物歧化酶最大增加134%，谷胱甘肽过氧化物酶最大增加220%）。这些变化在很大程度上先于广泛的足细胞突起收缩和肌动蛋白丝断裂的发展，这在第7天达到最大。这些结果表明，（1）PAN处理诱导足细胞ROS的显著早期变化，（2）足细胞可以对氧化应激进行抗氧化防御，（3）这种保护性反应在广泛的氧化剂诱导的足细胞结构损伤发生之前启动。这些发现表明，足细胞AOE活性的增强代表了一个潜在的治疗目标，以保护或改善肾病综合征期间足细胞损伤。
Background. An imbalance between the generation of reactive oxygen species (ROS) and antioxidant defense mechanisms has been suggested to play an important role in podocyte injury in nephrotic syndrome. Experimental nephrotic syndrome induced by injection of puromycin aminonucleoside (PAN) into rats is a well-established model of nephrotic syndrome, and can be largely prevented by pretreatment with antioxidant enzymes (AOE), suggesting that podocyte injury may be mediated by ROS.Methods. To test the hypothesis that PAN-induced podocyte injury is modulated in part by podocyte antioxidant defenses, we analyzed AOE activities, lipid peroxidation products, and relative ROS levels in podocytes using our recently reported in vitro model of PAN-induced podocyte injury.Results. PAN treatment induced early increases in both podocyte hydrogen peroxide and superoxide and later increases in lipid peroxidation products. Compared to baseline activities, PAN also induced significant changes in the major cellular AOE activities (maximum increases of 151% for catalase, 134% for superoxide dismutase, and 220% for glutathione peroxidase vs. time-matched controls). These changes largely preceded the development of extensive podocyte process retraction and actin filament disruption, which was maximal at 7 days.Conclusion. These results demonstrate that (1) PAN treatment induces significant early changes in podocyte ROS, (2) podocytes can mount an antioxidant defense against oxidant stress, and (3) this protective response is initiated prior to the development of extensive oxidant-induced podocyte structural injury. These findings suggest that enhancement of podocyte AOE activities represent a potential therapeutic target to protect from or ameliorate podocyte injury during nephrotic syndrome.