Mir-509-3p targets SLC25A13 to regulate ferroptosis and protect retinal endothelial cells in diabetic retinopathy.

IF 3.1 3区医学 Q2 ENDOCRINOLOGY & METABOLISM Acta Diabetologica Pub Date : 2024-11-07 DOI:10.1007/s00592-024-02400-3

Meiqing Ren, Qian Xu, Jie Luan, Yan Ni, Bo Xie

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Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Mir-509-3p 以 SLC25A13 为靶点，调节糖尿病视网膜病变中的铁蛋白沉积，保护视网膜内皮细胞。

目的：糖尿病视网膜病变（DR）是糖尿病的一种主要并发症，会导致视力损伤。本研究旨在探讨 miR-509-3p 在 DR 中的调控作用，重点研究其与 SLC25A13 的相互作用及其对视网膜内皮细胞功能、氧化应激、细胞凋亡和铁蛋白沉积的影响。方法：在高葡萄糖（HG）条件下培养 HRVECs 以建立体外 DR 模型。将 miR-509-3p 模拟物和抑制剂转染 HRVECs 以评估它们对 SLC25A13 表达、细胞活力、细胞凋亡、活性氧（ROS）水平和铁突变标志物的影响。荧光素酶报告试验和 RNA 免疫沉淀被用来证实 miR-509-3p 与 SLC25A13 mRNA 的结合。为了进行体内验证，将 agomiR-509-3p 注入 DR 小鼠的玻璃体内，评估视网膜厚度、病理损伤和细胞凋亡。在 HRVECs 中分析了铁色素沉着相关标记物（GPX4、TlR4、ASCL4），以探索 miR-509-3p 调节铁色素沉着的机制：结果：在体外，miR-509-3p 能显著降低 SLC25A13 的表达，从而提高 HRVEC 的存活率，减少细胞凋亡，降低 HG 条件下的 ROS 水平。SLC25A13 的过表达逆转了这些保护作用，而 miR-509-3p 的敲除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。结论：miR-509-3p 通过靶向 SLC25A13，减少视网膜内皮细胞的氧化应激、凋亡和铁蛋白沉积，在 DR 中发挥保护作用。这些发现凸显了 miR-509-3p 作为 DR 治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Diabetologica 医学-内分泌学与代谢

CiteScore

7.30

自引率

2.60%

发文量

180

审稿时长

2 months

期刊介绍： Acta Diabetologica is a journal that publishes reports of experimental and clinical research on diabetes mellitus and related metabolic diseases. Original contributions on biochemical, physiological, pathophysiological and clinical aspects of research on diabetes and metabolic diseases are welcome. Reports are published in the form of original articles, short communications and letters to the editor. Invited reviews and editorials are also published. A Methodology forum, which publishes contributions on methodological aspects of diabetes in vivo and in vitro, is also available. The Editor-in-chief will be pleased to consider articles describing new techniques (e.g., new transplantation methods, metabolic models), of innovative importance in the field of diabetes/metabolism. Finally, workshop reports are also welcome in Acta Diabetologica.