Activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress contributes to lead-induced nephrotoxicity

Wang, Min-Ge; Fan, Rui-Feng; Li, Wenhui; Zhang, Dong; Yang, Du-Bao; Wang, Zhenyong; Wang, Lin

doi:10.1016/j.bbamcr.2018.12.002

Cited by 51 publications

(34 citation statements)

References 40 publications

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“…PERK is structurally related to IRE1α and exists as a monomer under unstressed conditions ( 17 ). In the ER, the excessive abundance of proteins which are not folded correctly activates PERK via dimerization and auto-phosphorylation ( 18 ).…”

Section: Unfolded Protein Responsementioning

confidence: 99%

Unfolded Protein Response in Lung Health and Disease

Barabutis

2020

Front. Med.

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The unfolded protein response (UPR) is a complex element, destined to protect the cells against a diverse variety of extracellular and intracellular challenges. UPR activation devises highly efficient responses to counteract cellular threats. If those activities fail, it will dictate cellular execution. The current work focuses on the role of UPR in pulmonary function, by immersing into the highly interrelated network that operates toward the endothelial barrier function. A highly sophisticated UPR manipulation shall reveal new therapeutic possibilities against inflammatory lung disease, such as acute lung injury and acute respiratory distress syndrome.

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Section: Unfolded Protein Responsementioning

confidence: 99%

Unfolded Protein Response in Lung Health and Disease

Barabutis

2020

Front. Med.

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“…The ER pathway activation has been convincingly substantiated to injure various cells, including renal tubules epithelium in the presence of HG [6–8]. The present research first explored whether the effects of proper Pyr might robustly decrease expressions of these ER proteins in HG, which would be otherwise activated in the ER stress pathway and cause cell death (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Mild ER stress does not damage cells, but long‐term ER stress causes apoptosis [5]. Activation of the ER stress has been repeatedly demonstrated to damage cells, such as islets, nerves and renal tubules, in the presence of high glucose (HG), which is one of the important pathological processes of the diseases [6–8].…”

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confidence: 99%

Pyruvate alleviates high glucose‐induced endoplasmic reticulum stress and apoptosis in HK‐2 cells

et al. 2020

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Endoplasmic reticulum (ER) stress plays a critical role in the development of diabetic nephropathy (DN). We previously demonstrated that pyruvate (Pyr)‐enriched oral rehydration solution improved glucometabolic disorders and ameliorated DN outcome in db/db mice. Here, we investigated the effects of Pyr on high glucose‐induced ER stress and apoptosis in HK‐2 cells. Our results suggest that high glucose can induce reactive oxygen species production, apoptosis and ER stress in HK‐2 cells, and that Pyr treatment can ameliorate these effects and restore the expression of key proteins involved in ER stress. Thus, Pyr may have potential for the development of novel strategies for the prevention and treatment of clinical DN.

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“…It is consistent with this evidence, siRNA depletion of CHOP significantly decreased NaAsO 2 ‐induced DR5 mRNA level. In addition, CHOP expression has been reported to be closely related to ER stress and following PERK‐eIF2α‐ATF4 pathway 42 . The PERK‐eIF2α‐ATF4 pathway is activated to monitor the protein‐folding environment and to try to restore ER homeostasis when accumulation of misfolded proteins in the ER, if homeostasis imbalance is rescued, the activation of PERK‐eIF2α‐ATF4 pathway subsides.…”

Section: Discussionmentioning

confidence: 99%

ROS‐mediated PERK‐eIF2α‐ATF4 pathway plays an important role in arsenite‐induced L‐02 cells apoptosis via regulating CHOP‐DR5 signaling

Liu

Zhang

2020

Environmental Toxicology

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Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic‐induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated‐ER stress plays an important role in Life‐and‐Death decision of cells. The current study was to investigate whether NaAsO2 utilizes oxidative stress integrated‐ER stress signaling to exert pro‐apoptotic activity in L‐02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO2‐induced apoptosis by enhancing construction of the death‐inducing signaling complex (DISC). NaAsO2‐sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO2 increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R‐like ER kinase (PERK)‐eukaryotic translation initiation 2α (eIF2α)‐activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO2‐induced CHOP and DR5 expressions. In addition, the antioxidant N‐acetyl‐l‐cysteine (NAC) treatment led to amelioration of NaAsO2‐induced production of reactive oxygen species (ROS) and some ER stress‐ and apoptosis‐ related protein levels and cell viability. Taken together, the results indicate that ROS‐mediated PERK‐eIF2α‐ATF4 pathway activated by NaAsO2 is the critical upstream event for subsequent apoptosis induction via regulating CHOP‐DR5 signaling in L‐02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic‐induced hepatotoxicity.

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Activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress contributes to lead-induced nephrotoxicity

Cited by 51 publications

References 40 publications

Unfolded Protein Response in Lung Health and Disease

Unfolded Protein Response in Lung Health and Disease

Pyruvate alleviates high glucose‐induced endoplasmic reticulum stress and apoptosis in HK‐2 cells

ROS‐mediated PERK‐eIF2α‐ATF4 pathway plays an important role in arsenite‐induced L‐02 cells apoptosis via regulating CHOP‐DR5 signaling

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