MicroRNA-24 protects retina from degeneration in rats by down-regulating chitinase-3-like protein 1
MicroRNA-24 protects retina from degeneration in rats by down-regulating chitinase-3-like protein 1
复制标题
MicroRNA-24 通过下调几丁质酶 3 样蛋白 1 保护大鼠视网膜免于变性
DOI：
10.1016/j.exer.2019.107791
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发表时间：
2019-11-01
影响因子：
3.4
通讯作者：
Xu, Guo-Tong
中科院分区：
文献类型：
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作者：
Lian, Chunpin;Lou, Hui;Xu, Guo-Tong
MicroRNAs （miRNAs）已被证明在退行性视网膜疾病如年龄相关性黄斑变性（AMD）的发病和进展中发挥关键作用。在本研究中，我们首先证明miR-24通过靶向几丁质酶-3样蛋白1 （CHI3L1）在维持大鼠视网膜结构和视觉功能中发挥重要作用。在遗传性视网膜变性（RD）动物模型——英国皇家外科学院（RCS）大鼠的视网膜色素上皮（RPE）细胞中，miR-24较Sprague-Dawley （SD）大鼠低，CHI3L1水平较高。RCS大鼠眼睛的其他变化包括活化的AKT/mTOR和ERK通路以及RPE细胞的异常自噬。在RCS大鼠视网膜下注射agomiR-24进一步证实了miR-24和CHI3L1的作用，降低了CHI3L1的水平，保留了视网膜的结构和功能。上游，NF-kappa B被鉴定为这些大鼠RPE细胞中miR-24的调节因子。另一方面，在SD大鼠中，安塔哥米-24眼内处理引起的病理改变与RCS大鼠相似。结果揭示了miR-24对RPE细胞的保护作用，并提出了RCS大鼠RD的机制：细胞外应激刺激首先激活NF-kappa B信号通路，降低miR-24的表达，使CHI3L1升高。CHI3L1通过激活AKT/mTOR和ERIC通路导致异常自噬和RPE功能障碍。综上所述，尽管不能排除RCS大鼠的治疗作用是由miR-24调节的其他转录变化引起的可能性，但这些发现表明，miR-24通过靶向CHI3L1来保护大鼠视网膜。因此，miR-24和CHI3L1可能是开发更有效的治疗退行性视网膜疾病如AMD的靶点。
MicroRNAs (miRNAs) have been shown to play critical roles in the pathogenesis and progression of degenerative retinal diseases like age-related macular degeneration (AMD). In this study, we first demonstrated that miR-24 plays an important role in maintaining retinal structure and visual function of rats by targeting chitinase-3-like protein 1 (CHI3L1). In the retinal pigment epithelial (RPE) cells of Royal College of Surgeons (RCS) rats, an animal model of genetic retinal degeneration (RD), miR-24 was found lower and CHI3L1 level was higher in comparison with those in Sprague-Dawley (SD) rats. Other changes in the eyes of RCS rats include activated AKT/mTOR and ERK pathways and abnormal autophagy in the RPE cells. Such roles of miR-24 and CHI3L1 were further confirmed in RCS rats by subretinal injection of agomiR-24, which decreased CHI3L1 level and preserved retinal structure and function. Upstream, NF-kappa B was identified as the regulator of miR-24 in the RPE cells of these rats. On the other hand, in SD rats, intraocular treatment of antagomiR-24 induced pathological changes similar to those in RCS rats. The results revealed the protective roles for miR-24 to RPE cells and a mechanism for RD in RCS rats was proposed: extracellular stress stimuli first activate the NF-kappa B signaling pathway, which lowers miR-24 expression so that CHI3L1 increased. CHI3L1 sequentially results in aberrant autophagy and RPE dysfunction by activating AKT/mTOR and ERIC pathways. Taken together, although the possibility, that the therapeutic effects in RCS rats are caused by other transcriptional changes regulated by miR-24, cannot be excluded, these findings indicate that miR-24 protects rat retina by targeting CHI3L1. Thus, miR-24 and CHI3L1 might be the targets for developing more effective therapy for degenerative retinal diseases like AMD.