N 6-Methyladenosine demethylase FTO controls macrophage homeostasis in diabetic vasculopathy

IF 6.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Diabetes Pub Date : 2024-10-24 DOI:10.2337/db24-0691
Siguo Feng, Qiuyang Zhang, Qing Liu, Chang Huang, Huiying Zhang, Fengsheng Wang, Yue Zhu, Qizhi Jian, Xue Chen, Qin Jiang, Biao Yan
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Abstract

Diabetic vasculopathy, encompassing complications such as diabetic retinopathy, represents a significant source of morbidity, with inflammation playing a pivotal role in the progression of these complications. This study investigates the influence of m6A modification and the m6A demethylase FTO on macrophage polarization and its subsequent effects on diabetic microvasculopathy. We found that diabetes induces a shift in macrophage polarization towards a pro-inflammatory M1 phenotype, which is associated with a reduction in m6A modification levels. Notably, FTO emerges as a critical regulator of m6A under diabetic conditions. In vitro experiments reveal that FTO not only modulates macrophage polarization but also mediates their interactions with vascular endothelial cells. In vivo experiments demonstrate that FTO deficiency exacerbates retinal inflammation and microvascular dysfunction in diabetic retinas. Mechanistically, FTO stabilizes mRNA through an m6A-YTHDF2-dependent pathway, thereby activating the PI3K/AKT signaling cascade. Collectively, these findings position FTO as a promising therapeutic target for the management of diabetic vascular complications.
N 6-甲基腺苷去甲基化酶 FTO 控制糖尿病血管病变中巨噬细胞的稳态
糖尿病血管病变包括糖尿病视网膜病变等并发症,是发病率的重要来源,而炎症在这些并发症的发展过程中起着关键作用。本研究探讨了 m6A 修饰和 m6A 去甲基化酶 FTO 对巨噬细胞极化的影响及其随后对糖尿病微血管病变的影响。我们发现,糖尿病诱导巨噬细胞极化转向促炎的 M1 表型,这与 m6A 修饰水平的降低有关。值得注意的是,FTO 是糖尿病条件下 m6A 的关键调节因子。体外实验显示,FTO 不仅能调节巨噬细胞的极化,还能介导它们与血管内皮细胞的相互作用。体内实验证明,FTO 缺乏会加剧糖尿病视网膜炎症和微血管功能障碍。从机制上讲,FTO 通过依赖 m6A-YTHDF2 的途径稳定 mRNA,从而激活 PI3K/AKT 信号级联。总之,这些发现将 FTO 定位为治疗糖尿病血管并发症的一个有前景的治疗靶点。
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来源期刊
Diabetes
Diabetes 医学-内分泌学与代谢
CiteScore
12.50
自引率
2.60%
发文量
1968
审稿时长
1 months
期刊介绍: Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.
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