Circular Noncoding RNA NR3C1 Acts as a miR-382-5p Sponge to Protect RPE Functions via Regulating PTEN/AKT/mTOR Signaling Pathway
Circular Noncoding RNA NR3C1 Acts as a miR-382-5p Sponge to Protect RPE Functions via Regulating PTEN/AKT/mTOR Signaling Pathway
复制标题
环状非编码 RNA NR3C1 作为 miR-382-5p 海绵通过调节 PTEN/AKT/mTOR 信号通路保护 RPE 功能
DOI：
10.1016/j.ymthe.2020.01.010
复制
发表时间：
2020-03-04
影响因子：
12.4
通讯作者：
Liu, Qinghuai
中科院分区：
文献类型：
--
作者：
Chen, Xue;Jiang, Chao;Liu, Qinghuai
年龄相关性黄斑变性（AMD）是导致老年人不可逆失明的主要原因。视网膜色素上皮（RPE）细胞的去分化引发萎缩性AMD的早期病理事件。在此，我们的目的是研究来自NR3C1基因的环状RNA （circNR3C1）在调节RPE功能和amd发病机制中的作用。随着RPE的分化，circNR3C1表达持续上调，而在功能失调的RPE和AMD患者的血清中，circNR3C1表达下调。circNR3C1的沉默减少了RPE的特征转录本和蛋白质，中断了吞噬作用，加速了细胞内活性氧（ROS）的产生，促进了RPE在体外的增殖。circN3C1的沉默也降低了RPE特征标志物的表达，并扰乱了RPE的超微结构，表现为RPE增厚，基底褶皱和外节扭曲。机制上，circNR3C1作为内源性microRNA-382-5p （miR382-5p）海绵，隔离其活性，增加10号染色体上磷酸酶和紧张素同源物（PTEN）的表达，抑制蛋白激酶B/哺乳动物雷帕霉素靶蛋白（AKT/mTOR）通路。在体内和体外，miR-382-5p过表达和PTEN沉默模拟了circNR3C1沉默对RPE表型的影响。综上所述，circNR3C1通过直接海绵miR-382-5p阻断其与PTEN的相互作用，进而阻断AKT/mTOR通路，从而阻止AMD进展并保护RPE。药物circNR3C1补充剂是萎缩性AMD的有希望的治疗选择。
Age-related macular degeneration (AMD) is a universal leading cause for irreversible blindness in the elderly population. Dedifferentiation of retinal pigment epithelium (RPE) cells initiates early pathological events in atrophic AMD. Herein, we aim to investigate effects of a circular RNA derived from the NR3C1 gene (circNR3C1) on regulating RPE function and AMDpathogenesis. circNR3C1 expression was consistently upregulated along with RPE differentiation and was downregulated in dysfunctional RPE and blood serum of AMD patients. Silencing of circNR3C1 reduced RPE characteristic transcripts and proteins, interrupted phagocytosis, accelerated intracellular reactive oxygen species (ROS) generation, and promoted RPE proliferation in vitro. circN3C1 silencing also decreased expressions of RPE characteristic markers and disturbed the ultrastructure of RPE in vivo, as shown by a thickened RPE with twisted basal infoldings and outer segments. Mechanistically, circNR3C1 acted as an endogenous microRNA-382-5p (miR382-5p) sponge to sequester its activity, which increased phosphatase and tensin homolog on chromosome 10 (PTEN) expression and inhibited the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway. miR-382-5p overexpression and PTEN silencing mimicked effects of circNR3C1 silencing on RPE phenotypes in vivo and in vitro. In conclusion, circNR3C1 prevents AMD progression and protects RPE by directly sponging miR-382-5p to block its interaction with PTEN and subsequently blocks the AKT/mTOR pathway. Pharmacological circNR3C1 supplementations are promising therapeutic options for atrophic AMD.