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Title 

NQO1 deficiency leads enhanced autophagy in cisplatin-induced acute kidney injury through the AMPK/TSC2/mTOR signaling pathway

Authors 

T W KimY J KimH T KimS R ParkM Y LeeY D ParkChul Ho LeeJ Y Jung

Publisher 

Mary Ann Liebert

Issue Date 

2016

Citation 

Antioxidants and Redox Signaling, vol. 24, no. 15, pp. 867-883

Abstract 

Aims: 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. Results: 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. Innovation and Conclusion: 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

ISSN 

1523-0864

Link 

http://dx.doi.org/10.1089/ars.2015.6386

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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