Kim Tae-Won, Kim Young-Jung, Kim Hyun-Tae, Park Se-Ra, Lee Mee-Young, Park Yong-Deok, Lee Chul-Ho, Jung Ju-Young
1 Department of Veterinary Medicine, Institute of Veterinary Science, Chungnam National University , Daejeon, Republic of Korea.
2 Herbal Medicine Formulation Research Group, Korea Institute of Oriental Medicine , Daejeon, Republic of Korea.
Antioxid Redox Signal. 2016 May 20;24(15):867-83. doi: 10.1089/ars.2015.6386. Epub 2016 Apr 8.
Recent studies have revealed that autophagy is induced under various disease conditions; however, the role of autophagy in pathological states is controversial.
NAD(P)H: quinone oxidoreductase 1 (NQO1) is a highly inducible cytoprotective gene that regulates reactive oxygen species (ROS) generation. In this study, we examined whether NQO1 deficiency affects the autophagy process in response to cisplatin-induced nephrotoxicity.
In vitro, NQO1 and autophagy-associated proteins were induced after cisplatin treatment and the autophagosomes markedly increased in the cisplatin-treated NQO1-knockdown ACHN cells together with increased ROS production. In vivo, NQO1-KO mice displayed a significant increase in cisplatin-induced acute kidney injury (AKI), as indicated by elevated tubular damage and apoptosis as well as by suppressed cytoprotective signals. In agreement with the in vitro findings, NQO1-KO cisplatin-treated mice displayed a notable increase in autophagy-associated protein expression compared with their wild-type counterparts. Meanwhile, the expression of Ras-related protein 7, which participates in autophagosome maturation and lysosome fusion, markedly decreased in NQO1-KO mice, indicating hampered progress in late autophagy, and was accompanied by increased p62 protein expression. Moreover, NQO1 deletion enhanced the effect of the mammalian target of the rapamycin inhibitor, rapamycin, and led to enhanced tuberous sclerosis complex 2 phosphorylation through AMP-activated protein kinase activation.
These results indicate that autophagy may be enhanced to counter the increased stress due to NQO1 deficiency, an oxidative stress barrier. The present results demonstrate the significant influence of NQO1 on the autophagy process and support the hypothesis that autophagy plays a protective role under oxidative stress conditions. Antioxid. Redox Signal. 24, 867-883.
最近的研究表明，自噬在各种疾病状态下都会被诱导；然而，自噬在病理状态下的作用仍存在争议。
烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：醌氧化还原酶1（NQO1）是一种高度可诱导的细胞保护基因，可调节活性氧（ROS）的产生。在本研究中，我们研究了NQO1缺乏是否会影响顺铂诱导的肾毒性反应中的自噬过程。
在体外，顺铂处理后NQO1和自噬相关蛋白被诱导，在顺铂处理的NQO1敲低ACHN细胞中，自噬体明显增加，同时ROS产生增加。在体内，NQO1基因敲除小鼠顺铂诱导的急性肾损伤（AKI）显著增加，表现为肾小管损伤和凋亡增加以及细胞保护信号受到抑制。与体外研究结果一致，与野生型小鼠相比，NQO1基因敲除的顺铂处理小鼠自噬相关蛋白表达显著增加。同时，参与自噬体成熟和溶酶体融合的Ras相关蛋白7的表达在NQO1基因敲除小鼠中显著降低，表明晚期自噬进展受阻，并伴有p62蛋白表达增加。此外，NQO1缺失增强了雷帕霉素抑制剂雷帕霉素对哺乳动物雷帕霉素靶蛋白的作用，并通过AMP激活的蛋白激酶激活导致结节性硬化复合物2磷酸化增强。
这些结果表明，自噬可能会增强以应对由于NQO1缺乏（一种氧化应激屏障）导致的应激增加。目前的结果证明了NQO1对自噬过程的显著影响，并支持自噬在氧化应激条件下起保护作用的假说。《抗氧化与氧化还原信号》24卷，867 - 883页。
