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IRE1? siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro.

ABSTRACT: Diabetic peripheral neuropathy (DPN) is mainly characterized by demyelination resulted from the apoptosis of the Schwann cell (SCs). Although the exact mechanisms underlying DPN remain unclear, endoplasmic reticulum (ER) stress is strongly implicated in the apoptosis. Under ER stress, activated inositol-requiring kinase 1? (IRE1?) unregulated CHOP, phosphorylated JNK and Caspase-12 to aggravate apoptosis-mediated damage of DPN. Therefore, we tested the hypothesis that inhibition of IRE1? could reduce the ER stress-related apoptosis to relieve DPN. Here, we show that IRE1? siRNA improved the neurological morphology and function of DPN rats and rescued ER stress-related apoptosis in the sciatic nerve. Additionally, RSC96 cells transfected with IRE1? siRNA were used as in vitro model of DPN. It was found that IRE1? siRNA also decreased high glucose-induced apoptosis and inhibited ER stress-related apoptosis in the cells. Altogether, our results suggest that IRE1? should be considered a potential therapeutic agent for DPN.

SUBMITTER: Yao W

PROVIDER: S-EPMC5803253 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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IRE1α siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro.

Yao Weijie W Yang Xinwei X Zhu Jiayue J Gao Biane B Shi Haotian H Xu Liping L

Scientific reports 20180207 1

Diabetic peripheral neuropathy (DPN) is mainly characterized by demyelination resulted from the apoptosis of the Schwann cell (SCs). Although the exact mechanisms underlying DPN remain unclear, endoplasmic reticulum (ER) stress is strongly implicated in the apoptosis. Under ER stress, activated inositol-requiring kinase 1α (IRE1α) unregulated CHOP, phosphorylated JNK and Caspase-12 to aggravate apoptosis-mediated damage of DPN. Therefore, we tested the hypothesis that inhibition of IRE1α could r ...[more]

PMID: 29416111

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Project description:The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1?-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1? protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1? appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1? antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC-alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1? is activated in IBV-infected cells and serves as a survival factor during coronavirus infection.Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1?), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1? is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis.

Dataset Information

IRE1? siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro.

Publications

IRE1α siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro.

Similar Datasets

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