Ren Meiqing, Xu Qian, Luan Jie, Ni Yan, Xie Bo
Department of Ophthalmology, School of medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
The Diabetes Research Institute, Southeast University, Nanjing, 210009, China.
Acta Diabetol. 2024 Nov 7. doi: 10.1007/s00592-024-02400-3.
Diabetic retinopathy (DR) is a major complication of diabetes that leads to vision impairment. The aim of this study was to investigate the regulatory role of miR-509-3p in DR, focusing on its interaction with SLC25A13 and its impact on retinal endothelial cell function, oxidative stress, apoptosis, and ferroptosis.
HRVECs were cultured in high-glucose (HG) conditions to establish an in vitro DR model. miR-509-3p mimics and inhibitors were transfected into HRVECs to assess their effects on SLC25A13 expression, cell viability, apoptosis, reactive oxygen species (ROS) levels, and ferroptosis markers. A luciferase reporter assay and RNA immunoprecipitation were used to confirm the binding of miR-509-3p to SLC25A13 mRNA. For in vivo validation, agomiR-509-3p was injected into the vitreous of DR mice, and retinal thickness, pathological damage, and apoptosis were evaluated. Ferroptosis-related markers (GPX4, TlR4, ASCL4) were analyzed in HRVECs to explore the mechanism of miR-509-3p in regulating ferroptosis.
In vitro, miR-509-3p significantly decreased SLC25A13 expression, resulting in enhanced HRVEC viability, reduced apoptosis, and lower ROS levels under HG conditions. Overexpression of SLC25A13 reversed these protective effects, while miR-509-3p knockdown exacerbated oxidative stress and apoptosis. In vivo, agomiR-509-3p increased retinal thickness, reduced pathological damage, and decreased apoptosis in DR mice. Ferroptosis marker analysis revealed that miR-509-3p upregulated GPX4 expression and downregulated TlR4 and ASCL4, whereas SLC25A13 overexpression reversed these effects, further linking miR-509-3p to the regulation of ferroptosis.
miR-509-3p exerts a protective effect in DR by targeting SLC25A13, reducing oxidative stress, apoptosis, and ferroptosis in retinal endothelial cells. These findings highlight the potential of miR-509-3p as a therapeutic target for DR management.
糖尿病视网膜病变（DR）是糖尿病的一种主要并发症，可导致视力损害。本研究旨在探讨miR-509-3p在DR中的调控作用，重点关注其与SLC25A13的相互作用及其对视网膜内皮细胞功能、氧化应激、细胞凋亡和铁死亡的影响。
将人视网膜微血管内皮细胞（HRVECs）在高糖（HG）条件下培养，以建立体外DR模型。将miR-509-3p模拟物和抑制剂转染到HRVECs中，以评估它们对SLC25A13表达、细胞活力、细胞凋亡、活性氧（ROS）水平和铁死亡标志物的影响。采用荧光素酶报告基因检测和RNA免疫沉淀法来证实miR-509-3p与SLC25A13 mRNA的结合。为了进行体内验证，将agomiR-509-3p注射到DR小鼠的玻璃体内，并评估视网膜厚度、病理损伤和细胞凋亡情况。对HRVECs中的铁死亡相关标志物（GPX4、TlR4、ASCL4）进行分析，以探讨miR-509-3p调控铁死亡的机制。
在体外，miR-509-3p显著降低SLC25A13的表达，从而在HG条件下提高HRVEC的活力、减少细胞凋亡并降低ROS水平。SLC25A13的过表达逆转了这些保护作用，而miR-509-3p的敲低则加剧了氧化应激和细胞凋亡。在体内，agomiR-509-3p增加了DR小鼠的视网膜厚度，减少了病理损伤，并降低了细胞凋亡。铁死亡标志物分析显示，miR-509-3p上调了GPX4的表达，下调了TlR4和ASCL4，而SLC25A13的过表达则逆转了这些作用，进一步将miR-509-3p与铁死亡的调控联系起来。
miR-509-3p通过靶向SLC25A13发挥对DR的保护作用，减少视网膜内皮细胞中的氧化应激、细胞凋亡和铁死亡。这些发现突出了miR-509-3p作为DR治疗靶点的潜力。
