Blockade of mTORC1-NOX signaling pathway inhibits TGF-β1-mediated senescence-like structural alterations of the retinal pigment epithelium.

Szczegóły
Abstrakt

Tytuł:: Blockade of mTORC1-NOX signaling pathway inhibits TGF-β1-mediated senescence-like structural alterations of the retinal pigment epithelium.
Autorzy:: Lee SJ; Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Kim SJ; Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Jo DH; Department of Anatomy & Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Park KS; Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Kim JH; Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.; Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Republic of Korea.; Advanced Biomedical Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea.
Źródło:: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Mar; Vol. 35 (3), pp. e21403.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2020- : [Bethesda, Md.] : Hoboken, NJ : Federation of American Societies for Experimental Biology ; Wiley
Original Publication: [Bethesda, Md.] : The Federation, [c1987-
MeSH Terms:: Mechanistic Target of Rapamycin Complex 1/*physiology
NADPH Oxidases/*physiology
Retinal Pigment Epithelium/*pathology
Transforming Growth Factor beta1/*physiology
Animals ; Cells, Cultured ; Cellular Senescence ; Epithelial-Mesenchymal Transition ; Intravitreal Injections ; Macular Degeneration/drug therapy ; Macular Degeneration/metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; NADPH Oxidases/antagonists & inhibitors ; Pyrazolones/pharmacology ; Pyridones/pharmacology ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/physiology ; Signal Transduction/physiology
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Contributed Indexing:: Keywords: TGF-β1; epithelial-mesenchymal transition; mTORC1-NOX signaling; retinal pigment epithelium; senescence
Substance Nomenclature:: 0 (Pyrazolones)
0 (Pyridones)
0 (Reactive Oxygen Species)
0 (Transforming Growth Factor beta1)
45II35329V (setanaxib)
EC 1.6.3.- (NADPH Oxidases)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
Entry Date(s):: Date Created: 20210209 Date Completed: 20210726 Latest Revision: 20210726
Update Code:: 20240104
DOI:: 10.1096/fj.202001939RR
PMID:: 33559185
: Czasopismo naukowe

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-β1 (TGF-β1) 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-β1 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-β1-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-β1 increased endogenous expression of TGF-β1 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-β1 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-β-mTORC1-NOX signaling could be a potential therapeutic target for reducing pathogenic alterations in aged RPE and AMD.
(© 2021 Federation of American Societies for Experimental Biology.)

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