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视黄酸受体-α激动剂抑制视网膜色素上皮细胞的上皮-间充质转化。

Inhibition of epithelial-mesenchymal transition in retinal pigment epithelial cells by a retinoic acid receptor-α agonist.

机构信息

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube City, Yamaguchi, 755-8505, Japan.

出版信息

Sci Rep. 2021 Jun 4;11(1):11842. doi: 10.1038/s41598-021-90618-4.

DOI:10.1038/s41598-021-90618-4
PMID:34088917
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8178299/
Abstract

Epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a key role in proliferative retinal diseases such as age-related macular degeneration by contributing to subretinal fibrosis. To investigate the potential role of retinoic acid receptor-α (RAR-α) signaling in this process, we have now examined the effects of the RAR-α agonist Am580 on EMT induced by transforming growth factor-β2 (TGF-β2) in primary mouse RPE cells cultured in a three-dimensional type I collagen gel as well as on subretinal fibrosis in a mouse model. We found that Am580 inhibited TGF-β2-induced collagen gel contraction mediated by RPE cells. It also attenuated the TGF-β2-induced expression of the mesenchymal markers α-smooth muscle actin, fibronectin, and collagen type I; production of pro-matrix metalloproteinase 2 and interleukin-6; expression of the focal adhesion protein paxillin; and phosphorylation of SMAD2 in the cultured RPE cells. Finally, immunofluorescence analysis showed that Am580 suppressed both the TGF-β2-induced translocation of myocardin-related transcription factor-A (MRTF-A) from the cytoplasm to the nucleus of cultured RPE cells as well as subretinal fibrosis triggered by laser-induced photocoagulation in a mouse model. Our observations thus suggest that RAR-α signaling inhibits EMT in RPE cells and might attenuate the development of fibrosis associated with proliferative retinal diseases.

摘要

视网膜色素上皮 (RPE) 细胞中的上皮-间充质转化 (EMT) 通过促进视网膜下纤维化在年龄相关性黄斑变性等增殖性视网膜疾病中起着关键作用。为了研究视黄酸受体-α (RAR-α) 信号在这个过程中的潜在作用，我们现在研究了 RAR-α 激动剂 Am580 对 TGF-β2 诱导的原代培养的小鼠 RPE 细胞在三维 I 型胶原凝胶中 EMT 以及对小鼠模型中视网膜下纤维化的影响。我们发现 Am580 抑制了由 RPE 细胞介导的 TGF-β2 诱导的胶原凝胶收缩。它还减弱了 TGF-β2 诱导的间充质标志物 α-平滑肌肌动蛋白、纤连蛋白和 I 型胶原的表达；基质金属蛋白酶 2 和白细胞介素 6 的产生；粘着斑蛋白 paxillin 的表达；以及培养的 RPE 细胞中 SMAD2 的磷酸化。最后，免疫荧光分析表明，Am580 抑制了 TGF-β2 诱导的心肌营养素相关转录因子-A (MRTF-A) 从培养的 RPE 细胞的细胞质向细胞核的易位，以及激光诱导的光凝在小鼠模型中引发的视网膜下纤维化。因此，我们的观察结果表明 RAR-α 信号抑制 RPE 细胞中的 EMT，并可能减轻与增殖性视网膜疾病相关的纤维化的发展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/6b3abb30dd7c/41598_2021_90618_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/e438c3a1ceee/41598_2021_90618_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/0eea2278a115/41598_2021_90618_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/33d01f7e0459/41598_2021_90618_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/9fa2d0140806/41598_2021_90618_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/964ca87712f9/41598_2021_90618_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/e19aaa0d3598/41598_2021_90618_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/d5000a272e25/41598_2021_90618_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/6b3abb30dd7c/41598_2021_90618_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/e438c3a1ceee/41598_2021_90618_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/0eea2278a115/41598_2021_90618_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/33d01f7e0459/41598_2021_90618_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/9fa2d0140806/41598_2021_90618_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/964ca87712f9/41598_2021_90618_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/e19aaa0d3598/41598_2021_90618_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/d5000a272e25/41598_2021_90618_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ee7/8178299/6b3abb30dd7c/41598_2021_90618_Fig8_HTML.jpg

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