Attenuation of EMT in RPE cells and subretinal fibrosis by an RAR-γ agonist

Kazuhiro Kimura, Tomoko Orita, Yang Liu, Yang Yang, Kazuhiro Tokuda, Taishi Kurakazu, Takeshi Noda, Ryoji Yanai, Naoyuki Morishige, Atsunobu Takeda, Tatsuro Ishibashi, Koh Hei Sonoda

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Abstract

Abstract: Subretinal fibrosis contributes to the loss of vision associated with age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of AMD including the fibrotic reaction. We examined the role of retinoic acid receptor-γ (RAR-γ) in the epithelial-mesenchymal transition (EMT) and other fibrosis-related processes in mouse RPE cells cultured in a type I collagen gel. Transforming growth factor-β2 (TGF-β2)–induced collagen gel contraction mediated by the RPE cells was inhibited by the RAR-γ agonist R667 in a concentration- and time-dependent manner. Expression of the mesenchymal markers α-smooth muscle actin and fibronectin, the release of interleukin-6, and the phosphorylation of paxillin, mitogen-activated protein kinases (ERK, p38, and JNK), Smad2, and AKT induced by TGF-β2 were also suppressed by the RAR-γ agonist. Furthermore, gelatin zymography and immunoblot analysis revealed that the TGF-β2-induced release of matrix metalloproteinase (MMP)-2, MMP-3, MMP-8, and MMP-9 from RPE cells was inhibited by R667, and the MMP inhibitor GM6001 attenuated TGF-β2-induced RPE cell contraction. Finally, immunohistofluorescence analysis with antibodies to glial fibrillary acidic protein showed that R667 inhibited the development of subretinal fibrosis in a mouse model in vivo. Our results thus suggest that RAR-γ agonists may prove effective for the treatment of subretinal fibrosis associated with AMD. Key message: RAR-γ agonist R667 suppressed collagen gel contraction mediated by RPE cells.Epithelial-mesenchymal transition (EMT) in RPE cells was inhibited by RAR-γ agonist R667.RAR-γ agonist R667 inhibited fibrosis-related processes in RPE cells.RAR-γ agonists may attenuate AMD-associated fibrosis.

Original languageEnglish
Pages (from-to)749-758
Number of pages10
JournalJournal of Molecular Medicine
Volume93
Issue number7
DOIs
Publication statusPublished - Jul 22 2015

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Palovarotene
Retinoic Acid Receptors
Retinal Pigments
Epithelial-Mesenchymal Transition
Fibrosis
Epithelial Cells
Macular Degeneration
Transforming Growth Factors
Gels
Collagen
Matrix Metalloproteinase 8
Paxillin
Matrix Metalloproteinase 3
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 2
Glial Fibrillary Acidic Protein
Matrix Metalloproteinase 9
p38 Mitogen-Activated Protein Kinases
Gelatin
Collagen Type I

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Attenuation of EMT in RPE cells and subretinal fibrosis by an RAR-γ agonist. / Kimura, Kazuhiro; Orita, Tomoko; Liu, Yang; Yang, Yang; Tokuda, Kazuhiro; Kurakazu, Taishi; Noda, Takeshi; Yanai, Ryoji; Morishige, Naoyuki; Takeda, Atsunobu; Ishibashi, Tatsuro; Sonoda, Koh Hei.

In: Journal of Molecular Medicine, Vol. 93, No. 7, 22.07.2015, p. 749-758.

Research output: Contribution to journalArticle

Kimura, K, Orita, T, Liu, Y, Yang, Y, Tokuda, K, Kurakazu, T, Noda, T, Yanai, R, Morishige, N, Takeda, A, Ishibashi, T & Sonoda, KH 2015, 'Attenuation of EMT in RPE cells and subretinal fibrosis by an RAR-γ agonist', Journal of Molecular Medicine, vol. 93, no. 7, pp. 749-758. https://doi.org/10.1007/s00109-015-1289-8
Kimura, Kazuhiro ; Orita, Tomoko ; Liu, Yang ; Yang, Yang ; Tokuda, Kazuhiro ; Kurakazu, Taishi ; Noda, Takeshi ; Yanai, Ryoji ; Morishige, Naoyuki ; Takeda, Atsunobu ; Ishibashi, Tatsuro ; Sonoda, Koh Hei. / Attenuation of EMT in RPE cells and subretinal fibrosis by an RAR-γ agonist. In: Journal of Molecular Medicine. 2015 ; Vol. 93, No. 7. pp. 749-758.
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AU - Kimura, Kazuhiro

AU - Orita, Tomoko

AU - Liu, Yang

AU - Yang, Yang

AU - Tokuda, Kazuhiro

AU - Kurakazu, Taishi

AU - Noda, Takeshi

AU - Yanai, Ryoji

AU - Morishige, Naoyuki

AU - Takeda, Atsunobu

AU - Ishibashi, Tatsuro

AU - Sonoda, Koh Hei

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N2 - Abstract: Subretinal fibrosis contributes to the loss of vision associated with age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of AMD including the fibrotic reaction. We examined the role of retinoic acid receptor-γ (RAR-γ) in the epithelial-mesenchymal transition (EMT) and other fibrosis-related processes in mouse RPE cells cultured in a type I collagen gel. Transforming growth factor-β2 (TGF-β2)–induced collagen gel contraction mediated by the RPE cells was inhibited by the RAR-γ agonist R667 in a concentration- and time-dependent manner. Expression of the mesenchymal markers α-smooth muscle actin and fibronectin, the release of interleukin-6, and the phosphorylation of paxillin, mitogen-activated protein kinases (ERK, p38, and JNK), Smad2, and AKT induced by TGF-β2 were also suppressed by the RAR-γ agonist. Furthermore, gelatin zymography and immunoblot analysis revealed that the TGF-β2-induced release of matrix metalloproteinase (MMP)-2, MMP-3, MMP-8, and MMP-9 from RPE cells was inhibited by R667, and the MMP inhibitor GM6001 attenuated TGF-β2-induced RPE cell contraction. Finally, immunohistofluorescence analysis with antibodies to glial fibrillary acidic protein showed that R667 inhibited the development of subretinal fibrosis in a mouse model in vivo. Our results thus suggest that RAR-γ agonists may prove effective for the treatment of subretinal fibrosis associated with AMD. Key message: RAR-γ agonist R667 suppressed collagen gel contraction mediated by RPE cells.Epithelial-mesenchymal transition (EMT) in RPE cells was inhibited by RAR-γ agonist R667.RAR-γ agonist R667 inhibited fibrosis-related processes in RPE cells.RAR-γ agonists may attenuate AMD-associated fibrosis.

AB - Abstract: Subretinal fibrosis contributes to the loss of vision associated with age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of AMD including the fibrotic reaction. We examined the role of retinoic acid receptor-γ (RAR-γ) in the epithelial-mesenchymal transition (EMT) and other fibrosis-related processes in mouse RPE cells cultured in a type I collagen gel. Transforming growth factor-β2 (TGF-β2)–induced collagen gel contraction mediated by the RPE cells was inhibited by the RAR-γ agonist R667 in a concentration- and time-dependent manner. Expression of the mesenchymal markers α-smooth muscle actin and fibronectin, the release of interleukin-6, and the phosphorylation of paxillin, mitogen-activated protein kinases (ERK, p38, and JNK), Smad2, and AKT induced by TGF-β2 were also suppressed by the RAR-γ agonist. Furthermore, gelatin zymography and immunoblot analysis revealed that the TGF-β2-induced release of matrix metalloproteinase (MMP)-2, MMP-3, MMP-8, and MMP-9 from RPE cells was inhibited by R667, and the MMP inhibitor GM6001 attenuated TGF-β2-induced RPE cell contraction. Finally, immunohistofluorescence analysis with antibodies to glial fibrillary acidic protein showed that R667 inhibited the development of subretinal fibrosis in a mouse model in vivo. Our results thus suggest that RAR-γ agonists may prove effective for the treatment of subretinal fibrosis associated with AMD. Key message: RAR-γ agonist R667 suppressed collagen gel contraction mediated by RPE cells.Epithelial-mesenchymal transition (EMT) in RPE cells was inhibited by RAR-γ agonist R667.RAR-γ agonist R667 inhibited fibrosis-related processes in RPE cells.RAR-γ agonists may attenuate AMD-associated fibrosis.

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