NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury
NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury
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DOI：
10.1016/j.freeradbiomed.2012.07.012
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发表时间：
2012-09-15
影响因子：
7.4
通讯作者：
Yao, Jian
中科院分区：
文献类型：
--
作者：
Yan, Qiaojing;Gao, Kun;Yao, Jian
在嘌呤霉素诱导的大鼠肾病模型中，足细胞缝隙连接蛋白43(Cx43)的表达显著增加。然而，足细胞中改变的Cx43的机制和作用仍然不清楚。鉴于氧化应激在各种病理情况下介导足细胞损伤，我们研究了氧化应激相关机制可能参与Cx43的调节。用嘌呤霉素孵育足细胞会导致细胞活力的时间和浓度依赖性丧失，在此之前Cx43水平会升高。同时，嘌呤霉素还可诱导NOX4的表达，促进超氧化物(O-2)的产生。用apocynin和二苯基碘氯抑制NADPH氧化酶或加入超氧化物歧化酶模拟物Tempoll完全取消，而O2(中心点)供体甲萘二酮和2，3-二甲氧基-1，4-萘醌复制，嘌呤霉素对Cx43表达和细胞损伤的影响。进一步的分析表明，用几种结构不同的缝隙连接抑制剂处理足细胞，可以显著减弱嘌呤霉素的细胞毒性。因此，我们的结果表明，NADPH氧化酶介导的Cx43上调参与了足细胞损伤。(C)2012 Elsevier Inc.保留所有权利。
The gap junction protein connexin43 (Cx43) was markedly increased in podocytes in a rat model of nephrosis induced by puromycin. However, the mechanisms and roles of the altered Cx43 in podocytes are still unclear. Given that oxidative stress mediates podocyte injury under a variety of pathological situations, we examined the possible involvement of an oxidative stress-related mechanism in the regulation of Cx43. Incubation of podocytes with puromycin led to a time- and concentration-dependent loss of cell viability, which was preceded by an elevation in Cx43 levels. Concomitantly, puromycin also induced NOX4 expression and promoted superoxide (O-2(center dot-)) generation. Inhibition of NADPH oxidase with apocynin and diphenyleneiodonium chloride or addition of the superoxide dismutase mimetic tempol completely abrogated, whereas the O2(center dot-) donors menadione and 2,3-dimethoxy-1,4-naphthoquinone reproduced, the effects of puromycin on Cx43 expression and cell injury. Further analysis demonstrated that treatment of podocytes with several structurally different gap-junction inhibitors significantly attenuated the cytotoxicity of puromycin. Our results thus indicate that NADPH oxidase-mediated upregulation of Cx43 contributes to podocyte injury. (c) 2012 Elsevier Inc. All rights reserved.