Kawase Reiko, Nishimura Yuhei, Ashikawa Yoshifumi, Sasagawa Shota, Murakami Soichiro, Yuge Mizuki, Okabe Shiko, Kawaguchi Koki, Yamamoto Hiroshi, Moriyuki Kazumi, Yamane Shinsaku, Tsuruma Kazuhiro, Shimazawa Masamitsu, Hara Hideaki, Tanaka Toshio
Department of Molecular and Cellular Pharmacology, Pharmacogenomics, and Pharmacoinformatics, Mie University Graduate School of Medicine Tsu, Japan.
Department of Molecular and Cellular Pharmacology, Pharmacogenomics, and Pharmacoinformatics, Mie University Graduate School of MedicineTsu, Japan; Mie University Medical Zebrafish Research CenterTsu, Japan; Department of Systems Pharmacology, Mie University Graduate School of MedicineTsu, Japan; Department of Omics Medicine, Mie University Industrial Technology Innovation InstituteTsu, Japan; Department of Bioinformatics, Mie University Life Science Research CenterTsu, Japan.
Front Pharmacol. 2016 May 19;7:126. doi: 10.3389/fphar.2016.00126. eCollection 2016.
Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3-IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Müller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light-induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases.
视紫红质暴露于明亮的白光下可诱导光感受器细胞损伤和变性。然而，对光诱导视网膜病变潜在机制的全面理解仍然难以捉摸。在本研究中，我们对三种光诱导视网膜病变的啮齿动物模型进行了比较转录组分析，并鉴定出在所有三种模型中均失调的37个基因。基因本体分析表明，该基因集与由信号转导和转录激活因子1和3（STAT1/3）、白细胞介素6信号转导子（IL6ST）和抑瘤素M受体（OSMR）组成的细胞因子信号轴显著相关。此外，分析表明组蛋白乙酰转移酶EP300可能是STAT1/3-IL6ST/OSMR轴的关键上游调节因子。为了直接研究EP300的作用，我们构建了光诱导视网膜病变的斑马鱼幼体模型。利用该模型，我们证明了对EP300的药理学抑制在暴露于强光时显著增加视网膜细胞凋亡、减少光感受器细胞外节并增加假定的穆勒细胞的增殖。这些结果表明，EP300可能保护光感受器细胞免受光诱导的损伤，并且激活EP300可能是治疗视网膜退行性疾病的一种新的治疗方法。
