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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27 Citations (Scopus)

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

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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    Kimura, K., Orita, T., Liu, Y., Yang, Y., Tokuda, K., Kurakazu, T., Noda, T., Yanai, R., Morishige, N., Takeda, A., Ishibashi, T., & Sonoda, K. H. (2015). Attenuation of EMT in RPE cells and subretinal fibrosis by an RAR-γ agonist. Journal of Molecular Medicine, 93(7), 749-758. https://doi.org/10.1007/s00109-015-1289-8