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

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

  • Diabetes. 2024 Oct 24:db240691. doi: 10.2337/db24-0691.
Siguo Feng 1 2,  Qiuyang Zhang 1 2,  Qing Liu 1 2,  Chang Huang 3,  Huiying Zhang 1 2,  Fengsheng Wang 1 2,  Yue Zhu 1 2,  Qizhi Jian 4,  Xue Chen 5,  Qin Jiang 1 2,  Biao Yan 4
Affiliations

Affiliations

  • 1 The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
  • 2 The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 3 Eye Institute and Department of Ophthalmology, Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
  • 4 Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
PMID: 39446524 DOI: 10.2337/db24-0691
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.

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