Suppression of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells by an MRTF-A Inhibitor
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- Masaaki Kobayashi
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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- Kazuhiro Tokuda
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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- Yuka Kobayashi
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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- Chiemi Yamashiro
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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- Sho-Hei Uchi
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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- Makoto Hatano
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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- Kazuhiro Kimura
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
この論文をさがす
説明
Epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells is related to the pathogenesis of subretinal fibrosis such as that associated with macular degeneration. The role of myocardin-related transcription factor A (MRTF-A) in EMT of RPE cells and subretinal fibrosis was investigated.The migratory activity of human RPE-1 cells in culture was evaluated using a scratch assay. The subcellular distribution of MRTF-A in RPE-1 cells, as well as the extent of subretinal fibrosis in a mouse model, were determined by immunofluorescence analysis. Expression of α-smooth muscle actin (α-SMA), collagen type I (COL1), connective tissue growth factor (CTGF), and paxillin was examined by immunoblot analysis or reverse transcription and quantitative polymerase chain reaction analysis, whereas that of pro-matrix metalloproteinase-2 (MMP-2) was assessed by gelatin zymography.The MRTF-A signaling inhibitor CCG-1423 suppressed RPE-1 cell migration in a concentration-dependent manner. Transforming growth factor-beta (TGF-β2) induced MRTF-A translocation from the cytoplasm to the nucleus of RPE-1 cells, and this effect was attenuated by CCG-1423. TGF-β2 up-regulated the abundance of α-SMA, paxillin, and pro-MMP-2 proteins as well as the amounts of α-SMA, COL1, and CTGF mRNAs in a manner sensitive to inhibition by CCG-1423. Finally, intravitreal injection of CCG-1423 markedly attenuated the development of subretinal fibrosis induced by photocoagulation in vivo.Our results implicate MRTF-A in EMT of RPE cells and in the development of subretinal fibrosis in vivo, suggesting that MRTF-A is a potential therapeutic target for retinal diseases characterized by subretinal fibrosis.
収録刊行物
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- Investigative Opthalmology & Visual Science
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Investigative Opthalmology & Visual Science 60 (2), 528-, 2019-02-01
Association for Research in Vision and Ophthalmology (ARVO)
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キーワード
- Epithelial-Mesenchymal Transition
- Dose-Response Relationship, Drug
- Connective Tissue Growth Factor
- Retinal Pigment Epithelium
- Real-Time Polymerase Chain Reaction
- Fibrosis
- Actins
- Collagen Type I
- Retina
- Mice, Inbred C57BL
- Disease Models, Animal
- Mice
- Cell Movement
- Benzamides
- Trans-Activators
- Animals
- Humans
- Matrix Metalloproteinase 2
- Anilides
- Female
- Fluorescent Antibody Technique, Indirect
詳細情報 詳細情報について
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- CRID
- 1360004236545868160
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- ISSN
- 15525783
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- PubMed
- 30707754
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- 資料種別
- journal article
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- データソース種別
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- Crossref
- KAKEN
- OpenAIRE