Journal of Molecular Medicine

, Volume 93, Issue 7, pp 749–758 | Cite as

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

  • Kazuhiro KimuraEmail author
  • Tomoko Orita
  • Yang Liu
  • Yang Yang
  • Kazuhiro Tokuda
  • Taishi Kurakazu
  • Takeshi Noda
  • Ryoji Yanai
  • Naoyuki Morishige
  • Atsunobu Takeda
  • Tatsuro Ishibashi
  • Koh-Hei Sonoda
Original Article


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.


Retinal pigment epithelial cell Transforming growth factor-β (TGF-β) Epithelial-mesenchymal transition Extracellular matrix Subretinal fibrosis Age-related macular degeneration 



This study was supported by Takeda Science Foundation. We thank Yukari Mizuno and Shizuka Murata for technical assistance.

Disclosure statement

The authors declare no conflicts of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kazuhiro Kimura
    • 1
    Email author
  • Tomoko Orita
    • 1
  • Yang Liu
    • 1
  • Yang Yang
    • 2
  • Kazuhiro Tokuda
    • 1
  • Taishi Kurakazu
    • 1
  • Takeshi Noda
    • 1
  • Ryoji Yanai
    • 1
  • Naoyuki Morishige
    • 1
  • Atsunobu Takeda
    • 2
  • Tatsuro Ishibashi
    • 2
  • Koh-Hei Sonoda
    • 1
  1. 1.Department of OphthalmologyYamaguchi University Graduate School of MedicineUbe CityJapan
  2. 2.Department of Ophthalmology, Graduate School of Medical SciencesKyushu UniversityHigashi-kuJapan

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