<i>NQO1</i>Deficiency Leads Enhanced Autophagy in Cisplatin-Induced Acute Kidney Injury Through the AMPK/TSC2/mTOR Signaling Pathway

Kim, Tae−Won; Kim, Young-Jung; Kim, Hyun-Tae; Park, Se-Ra; Lee, Mee-Young; Park, Yong-Deok; Lee, Chul‐Ho; Jung, Ju‐Young

doi:10.1089/ars.2015.6386

Cited by 39 publications

(32 citation statements)

References 48 publications

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“…Furthermore, More recent evidence highlights that the TSC2-mTOR signaling feeds into the AMPK pathway (Kim et al 2016;Tanwar et al 2012;Zhao et al 2015). The present study revealed that treatment of NP robustly phosphorylated and activated AMPK, and simultaneously suppressed TSC2 and mTOR activity in testis.…”

Section: Discussionmentioning

confidence: 99%

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Duan

Quan

et al. 2017

Toxicology Letters

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The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100 mg/kg body weight/2 days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis. Furthermore, 10 µM Compound C or AMPKα1 siRNA pre-treatment effectively attenuated autophagy and reversed AMPK-mTOR-p70S6K/4EBP1 signaling in NP-treated SCs. Co-treatment with 1 mM AICAR remarkably strengthened NP-induced autophagy and mTOR inhibition in SCs. Together, these data suggest that NP stimulates Sertoli cell autophagy and inhibits mTOR-p70S6K/4EBP1 activity through AMPK activation, which is the potential mechanism responsible for the regulation of testis function and differentiation following NP exposure.

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Section: Discussionmentioning

confidence: 99%

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Duan

Quan

et al. 2017

Toxicology Letters

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“…Notably, the expression of NQO1 was closely related to Nrf2-mediated inhibition of the NLRP3 inflammasome, which indicated that Nrf2-induced NQO1 expression played a critical role in scavenging ROS. In addition, NQO1 was identified as a highly inducible cytoprotective gene that regulated ROS generation (21). tBHQ could ameliorate arsenic-induced cytotoxicity and apoptosis by inducing Nrf2-dependent antioxidant responses in which NQO1 was Cytospin preparation followed by HE staining was performed (G).…”

Section: Il-1b Was Detected By Elisa (D) Wt Bmdms and Nrf2mentioning

confidence: 99%

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

Liu

Zhang

Ding

et al. 2017

Antioxidants & Redox Signaling

193

140

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Aims: The NLRP3 inflammasome is a multiprotein complex that protects hosts against a variety of pathogens. However, the molecular mechanisms of modulating NLRP3 inflammasome activation, especially at the priming step, are still poorly understood. This study was designed to elucidate the negative regulation of nuclear factor E2-related factor-2 (Nrf2) on the activation of NLRP3 inflammasome. Results: We reported that Nrf2 activation inhibited NLRP3 expression, caspase-1 cleavage, and subsequent IL-1b generation. Compared with normal cells, Nrf2-deficient cells showed upregulated cleaved caspase-1, which were attributed to the increased transcription of NLRP3 caused by excess reactive oxygen species (ROS). Furthermore, priming of the NLRP3 inflammasome was sensitive to the exogenous ROS levels induced by H 2 O 2 or rotenone. Combined with adenosine triphosphate, rotenone triggered higher activity of the NLRP3 inflammasome compared with lipopolysaccharide, suggesting that ROS promoted the priming step. In addition, Nrf2-induced NQO1 was involved in the inhibition of the NLRP3 inflammasome. In an in vivo alum-induced peritonitis mouse model, Nrf2 activation suppressed typical IL-1 signaling-dependent inflammation, whereas Nrf2 -/-mice exhibited a significant increase in the recruitment of immune cell and the generation of IL-1b compared with wild-type mice. Innovation: We elucidated the effects and possible mechanisms of Nrf2 activation-induced NQO1 expression on NLRP3 inflammasome inactivation and established a novel regulatory role of the Nrf2 pathway in ROSinduced NLRP3 priming. Conclusions: We demonstrated Nrf2 negatively regulating NLRP3 inflammasome activity by inhibiting the priming step and suggested that Nrf2 could be a potential target for some uncontrolled inflammasome activation-associated diseases. Antioxid. Redox Signal. 26,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]

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“…Requires stimuli/ intervention to determine autophagic flux. [6][7][8][9][10][11][12][13][14]16,17 Immuno-histochemistry Suitable for studying protein expression changes within specific regions of the renal cortex.…”

Section: Methodsmentioning

confidence: 99%

“…11,12 The significance of autophagy and the role it plays in the development of renal pathology has risen to prominence in recent years, but few have addressed changes in autophagic flux in vivo. [6][7][8][9][10][11][12][13][14][15][16][17][18] Many investigations have attempted to address perturbations in autophagy activity without addressing the fundamental question of whether autophagic flux is altered under the pathological milieu that is being studied.…”

Section: Introductionmentioning

confidence: 99%

Methods in renal research: Measurement of autophagic flux in the renal cortex ex vivo

2018

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The role of autophagy in the kidney and many nephrological diseases has gained prominence in recent years. Much of this research has been focused on markers of autophagy that are static and reveal little about the state of this dynamic pathway. Other mechanistic investigations are limited to in vitro studies, that often provide circumstantial evidence of autophagic flux. Here we describe a method for measuring autophagic flux ex vivo that allows more direct observations to be made in situ regarding the state of autophagic flux within the renal cortex of a single animal.

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NQO1Deficiency Leads Enhanced Autophagy in Cisplatin-Induced Acute Kidney Injury Through the AMPK/TSC2/mTOR Signaling Pathway

Cited by 39 publications

References 48 publications

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

Methods in renal research: Measurement of autophagic flux in the renal cortex ex vivo

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