Transforming Growth Factor beta 1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis
DC Field | Value | Language |
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dc.contributor.author | Das, Ranjan | - |
dc.contributor.author | Xu, Shanhua | - |
dc.contributor.author | Tuyet Thi Nguyen | - |
dc.contributor.author | Quan, Xianglan | - |
dc.contributor.author | Choi, Seong-Kyung | - |
dc.contributor.author | Kim, Soo-Jin | - |
dc.contributor.author | Lee, Eun Young | - |
dc.contributor.author | Cha, Seung-Kuy | - |
dc.contributor.author | Park, Kyu-Sang | - |
dc.date.accessioned | 2021-08-11T19:24:03Z | - |
dc.date.available | 2021-08-11T19:24:03Z | - |
dc.date.issued | 2015-12-25 | - |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.issn | 1083-351X | - |
dc.identifier.uri | https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/9960 | - |
dc.description.abstract | TGF-beta is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-beta 1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-beta 1-induced apoptosis in immortalized podocytes. TGF-beta 1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-beta receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTOR Delta augmented TGF-beta 1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition ofmTORC1by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-beta 1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-beta 1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-beta 1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-beta 1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-beta 1-induced ERK1/2-mTOR activation. Our data suggest that TGF-beta 1 increases translation of Nox4 through the Smad-ERK1/2-mTORC1 axis, which is independent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases. | - |
dc.format.extent | 13 | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | American Society for Biochemistry and Molecular Biology Inc. | - |
dc.title | Transforming Growth Factor beta 1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis | - |
dc.type | Article | - |
dc.publisher.location | 미국 | - |
dc.identifier.doi | 10.1074/jbc.M115.703116 | - |
dc.identifier.scopusid | 2-s2.0-84951802363 | - |
dc.identifier.wosid | 000367199000016 | - |
dc.identifier.bibliographicCitation | Journal of Biological Chemistry, v.290, no.52, pp 30830 - 30842 | - |
dc.citation.title | Journal of Biological Chemistry | - |
dc.citation.volume | 290 | - |
dc.citation.number | 52 | - |
dc.citation.startPage | 30830 | - |
dc.citation.endPage | 30842 | - |
dc.type.docType | Article | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | sci | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.subject.keywordPlus | EPITHELIAL-MESENCHYMAL TRANSITION | - |
dc.subject.keywordPlus | TGF-BETA | - |
dc.subject.keywordPlus | DIABETIC-NEPHROPATHY | - |
dc.subject.keywordPlus | TUBEROUS SCLEROSIS | - |
dc.subject.keywordPlus | MTORC1 ACTIVATION | - |
dc.subject.keywordPlus | OXIDATIVE STRESS | - |
dc.subject.keywordPlus | NADPH OXIDASE | - |
dc.subject.keywordPlus | UP-REGULATION | - |
dc.subject.keywordPlus | PHOSPHORYLATION | - |
dc.subject.keywordPlus | PATHWAY | - |
dc.subject.keywordAuthor | ERK | - |
dc.subject.keywordAuthor | NADPH oxidase | - |
dc.subject.keywordAuthor | SMAD transcription factor | - |
dc.subject.keywordAuthor | TGF-β | - |
dc.subject.keywordAuthor | apoptosis | - |
dc.subject.keywordAuthor | mammalian target of rapamycin (mTOR) | - |
dc.subject.keywordAuthor | podocyte | - |
dc.subject.keywordAuthor | reactive oxygen species (ROS) | - |
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