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Blockade of mTORC1-NOX signaling pathway inhibits TGF-β1-mediated senescence-like structural alterations of the retinal pigment epithelium : Blockade of mTORC1-NOX signaling pathway inhibits TGF-beta 1-mediated senescence-like structural alterations of the retinal pigment epithelium
DC Field | Value | Language |
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dc.contributor.author | Lee, Seok Jae | - |
dc.contributor.author | Kim, Soo-Jin | - |
dc.contributor.author | Jo, Dong Hyun | - |
dc.contributor.author | Park, Kyu-Sang | - |
dc.contributor.author | Kim, Jeong Hun | - |
dc.date.accessioned | 2023-04-25T07:30:36Z | - |
dc.date.available | 2023-04-25T07:30:36Z | - |
dc.date.created | 2021-06-03 | - |
dc.date.created | 2021-06-03 | - |
dc.date.issued | 2021-03 | - |
dc.identifier.citation | FASEB Journal, Vol.35 No.3, p. e21403 | - |
dc.identifier.issn | 0892-6638 | - |
dc.identifier.uri | https://hdl.handle.net/10371/191479 | - |
dc.description.abstract | The retinal pigment epithelium (RPE) undergoes characteristic structural changes and epithelial-mesenchymal transition (EMT) during normal aging, which are exacerbated in age-related macular degeneration (AMD). Although the pathogenic mechanisms of aging and AMD remain unclear, transforming growth factor-beta 1 (TGF-beta 1) is known to induce oxidative stress, morphometric changes, and EMT as a senescence-promoting factor. In this study, we examined whether intravitreal injection of TGF-beta 1 into the mouse eye elicits senescence-like morphological alterations in the RPE and if this can be prevented by suppressing mammalian target of rapamycin complex 1 (mTORC1) or NADPH oxidase (NOX) signaling. We verified that intravitreal TGF-beta 1-induced stress fiber formation and EMT in RPE cells, along with age-associated morphometric changes, including increased variation in cell size and reduced cell density. In RPE cells, exogenous TGF-beta 1 increased endogenous expression of TGF-beta 1 and upregulated Smad3-ERK1/2-mTORC1 signaling, increasing reactive oxygen species (ROS) production and EMT. We demonstrated that inhibition of the mTORC1-NOX4 pathway by pretreatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-dependent protein kinase, or GKT137831, a NOX1/4 inhibitor, decreased ROS generation, prevented stress fiber formation, attenuated EMT, and improved the regularity of the RPE structure in vitro and in vivo. These results suggest that intravitreal TGF-beta 1 injection could be used as a screening model to investigate the aging-related structural and functional changes to the RPE. Furthermore, the regulation of TGF-beta-mTORC1-NOX signaling could be a potential therapeutic target for reducing pathogenic alterations in aged RPE and AMD. | - |
dc.language | 영어 | - |
dc.publisher | Federation of American Societies for Experimental Biology | - |
dc.title | Blockade of mTORC1-NOX signaling pathway inhibits TGF-β1-mediated senescence-like structural alterations of the retinal pigment epithelium | - |
dc.title.alternative | Blockade of mTORC1-NOX signaling pathway inhibits TGF-beta 1-mediated senescence-like structural alterations of the retinal pigment epithelium | - |
dc.type | Article | - |
dc.identifier.doi | 10.1096/fj.202001939RR | - |
dc.citation.journaltitle | FASEB Journal | - |
dc.identifier.wosid | 000629576700028 | - |
dc.identifier.scopusid | 2-s2.0-85101380477 | - |
dc.citation.number | 3 | - |
dc.citation.startpage | e21403 | - |
dc.citation.volume | 35 | - |
dc.description.isOpenAccess | N | - |
dc.contributor.affiliatedAuthor | Jo, Dong Hyun | - |
dc.contributor.affiliatedAuthor | Kim, Jeong Hun | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordAuthor | epithelial& | - |
dc.subject.keywordAuthor | #8208 | - |
dc.subject.keywordAuthor | mesenchymal transition | - |
dc.subject.keywordAuthor | retinal pigment epithelium | - |
dc.subject.keywordAuthor | senescence | - |
dc.subject.keywordAuthor | TGF& | - |
dc.subject.keywordAuthor | #8208 | - |
dc.subject.keywordAuthor | & | - |
dc.subject.keywordAuthor | #946 | - |
dc.subject.keywordAuthor | 1 | - |
dc.subject.keywordAuthor | mTORC1& | - |
dc.subject.keywordAuthor | #8208 | - |
dc.subject.keywordAuthor | NOX signaling | - |
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