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

被引：72

作者：

Kimura, Kazuhiro ^{[1
]}

Orita, Tomoko ^{[1
]}

Liu, Yang ^{[1
]}

Yang, Yang ^{[2
]}

Tokuda, Kazuhiro ^{[1
]}

Kurakazu, Taishi ^{[1
]}

Noda, Takeshi ^{[1
]}

Yanai, Ryoji ^{[1
]}

Morishige, Naoyuki ^{[1
]}

Takeda, Atsunobu ^{[2
]}

Ishibashi, Tatsuro ^{[2
]}

Sonoda, Koh-Hei ^{[1
]}

机构：

[1] Yamaguchi Univ, Grad Sch Med, Dept Ophthalmol, Ube, Yamaguchi 7558505, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Higashi Ku, Fukuoka 8128582, Japan

来源：

JOURNAL OF MOLECULAR MEDICINE-JMM | 2015年 / 93卷 / 07期

关键词：

Retinal pigment epithelial cell; Transforming growth factor-beta (TGF-beta); Epithelial-mesenchymal transition; Extracellular matrix; Subretinal fibrosis; Age-related macular degeneration; GROWTH-FACTOR-BETA; PIGMENT EPITHELIAL-CELLS; HUMAN TENON FIBROBLASTS; TRANS-RETINOIC ACID; MACULAR DEGENERATION; PROLIFERATIVE VITREORETINOPATHY; MESENCHYMAL TRANSITION; CONTRACTION; INHIBITION; INDUCTION;

D O I：

10.1007/s00109-015-1289-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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-gamma (RAR-gamma) 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-beta 2 (TGF-beta 2)-induced collagen gel contraction mediated by the RPE cells was inhibited by the RAR-gamma agonist R667 in a concentration- and time-dependent manner. Expression of the mesenchymal markers alpha-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-beta 2 were also suppressed by the RAR-gamma agonist. Furthermore, gelatin zymography and immunoblot analysis revealed that the TGF-beta 2-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-beta 2-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-gamma agonists may prove effective for the treatment of subretinal fibrosis associated with AMD.

引用

页码：749 / 758

页数：10

共 39 条

[1] GROWTH-FACTORS IN VITREOUS AND SUBRETINAL FLUID CELLS FROM PATIENTS WITH PROLIFERATIVE VITREORETINOPATHY [J].