MiR-455-5p ameliorates HG-induced apoptosis, oxidative stress and inflammatory via targeting SOCS3 in retinal pigment epithelial cells
MiR-455-5p ameliorates HG-induced apoptosis, oxidative stress and inflammatory via targeting SOCS3 in retinal pigment epithelial cells
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DOI：
10.1002/jcp.28755
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Lei, Yi
中科院分区：
文献类型：
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作者：
Chen, Pan;Miao, Ying;Lei, Yi
糖尿病视网膜病变（DR）仍然是成人糖尿病患者失明的主要原因。本研究的主要目的是探讨miR-455- 5 p在高糖处理的视网膜色素上皮（RPE）细胞中的作用及其机制。本研究发现，HG刺激ARPE-19细胞后，miR-455- 5 p的表达明显下调。此外，miR-455- 5 p的强制表达显着提高细胞活力，抑制HG诱导的凋亡，伴随着降低BCL 2相关X蛋白（Bax）/B细胞白血病/淋巴瘤2（Bcl-2）的比例和凋亡标志物裂解的caspase-3的表达在HG攻击。随后，增加miR-455- 5 p显著减轻HG触发的氧化应激损伤，反映为降低细胞内活性氧（ROS）和丙二醛（MDA）含量以及NADPH氧化酶4表达，同时增强HG刺激的超氧化物歧化酶、过氧化氢酶和GPX的活性。此外，miR-455- 5 p的增强表达有效地改善了HG刺激的炎症反应，如通过抑制HG攻击的ARPE-19细胞中炎性细胞因子白细胞介素1 β（IL-1 β）、IL-6和肿瘤坏死因子-α的分泌所例示的。最重要的是，我们成功鉴定了细胞因子信号转导抑制因子3（SOCS 3）作为miR-455- 5 p的直接靶基因，并且miR-455- 5 p负调控SOCS 3的表达。从机制上讲，SOCS 3的恢复消除了miR-455- 5 p对细胞凋亡、ROS积累和炎症因子产生的有益作用。综上所述，这些发现表明miR-455- 5 p通过靶向SOCS 3抑制细胞凋亡、氧化应激和炎症反应来减轻HG诱导的损伤。这项研究表明，miR-455- 5 p可能成为DR治疗的新的潜在治疗药物。
Diabetic retinopathy (DR) remains the leading cause of blindness in adults with diabetes mellitus. Numerous microRNAs (miRNAs) have been identified to modulate the pathogenesis of DR. The main purpose of this study was to evaluate the potential roles of miR-455-5p in high glucose (HG)-treated retinal pigment epithelial (RPE) cells and underlying mechanisms. Our present investigation discovered that the expression of miR-455-5p was apparently downregulated in ARPE-19 cells stimulated with HG. In addition, forced expression of miR-455-5p markedly enhanced cell viability and restrained HG-induced apoptosis accompanied by decreased BCL2-associated X protein (Bax)/B-cell leukemia/lymphoma 2 (Bcl-2) ratio and expression of apoptotic marker cleaved caspase-3 during HG challenged. Subsequently, augmentation of miR-455-5p remarkably alleviated HG-triggered oxidative stress injury as reflected by decreased the production of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content as well as NADPH oxidase 4 expression, concomitant with enhanced the activities of superoxide dismutase, catalase, and GPX stimulated with HG. Furthermore, enforced expression of miR-455-5p effectively ameliorated HG-stimulated inflammatory response as exemplified by repressing the secretion of inflammatory cytokines interleukin 1 beta (IL-1 beta), IL-6, and tumour necrosis factor-alpha in ARPE-19 cells challenged by HG. Most importantly, we successfully identified suppressor of cytokine signaling 3 (SOCS3) as a direct target gene of miR-455-5p, and miR-455-5p negatively regulated the expression of SOCS3. Mechanistically, restoration of SOCS3 abrogated the beneficial effects of miR-455-5p on apoptosis, accumulation of ROS, and inflammatory factors production in response to HG. Taken together, these findings demonstrated that miR-455-5p relieved HG-induced damage through repressing apoptosis, oxidant stress, and inflammatory response by targeting SOCS3. The study gives evidence that miR-455-5p may serve as a new potential therapeutic agent for DR treatment.