Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China; Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200032, China.
Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
Metabolism. 2022 Nov;136:155293. doi: 10.1016/j.metabol.2022.155293. Epub 2022 Aug 19.
Diabetic retinopathy (DR) is one of the leading causes of severe visual impairment worldwide. However, the role of adaptive immune inflammation driven by microglia/macrophages in DR is not yet well elucidated. Kdm6a is a histone demethylase that removes the trimethyl groups of histones H3K27 and plays important biological roles in activating target genes. To elucidate the role of Kdm6a in microglia/macrophages in diabetic retinas, we established diabetic animal models with conditional knockout mice to investigate the impacts of Kdm6a deficiency. The RNA-seq analysis, mass spectrum examination, immunohistochemistry and detection of enzyme activities were used to elucidate the effect of Kdm6a deletion on gene transcription in microglia/macrophages. The expression of Kdm6a was increased in the retinas of diabetic mice compared to the control group. Loss of Kdm6a in microglia/macrophages ameliorated the diabetes-induced retinal thickness decrease, inflammation, and visual impairment. Kdm6a in microglia/macrophages regulated Lcn2 expression in a demethylase activity-dependent manner and inhibited glycolysis progression in photoreceptor cells through Lcn2. These results suggest that Kdm6a in microglia/macrophages aggravated diabetic retinopathy by promoting the expression of Lcn2 and impairing glycolysis progression in photoreceptor cells.
糖尿病性视网膜病变（DR）是全球导致严重视力损害的主要原因之一。然而，由小胶质细胞/巨噬细胞驱动的适应性免疫炎症在 DR 中的作用尚未得到充分阐明。Kdm6a 是一种组蛋白去甲基酶，可去除组蛋白 H3K27 的三甲基基团，并在激活靶基因方面发挥重要的生物学作用。为了阐明 Kdm6a 在糖尿病视网膜中小胶质细胞/巨噬细胞中的作用，我们建立了条件性敲除小鼠的糖尿病动物模型，以研究 Kdm6a 缺失的影响。我们通过 RNA-seq 分析、质谱检查、免疫组织化学和酶活性检测来阐明 Kdm6a 缺失对小胶质细胞/巨噬细胞中转录基因的影响。与对照组相比，糖尿病小鼠视网膜中的 Kdm6a 表达增加。小胶质细胞/巨噬细胞中 Kdm6a 的缺失减轻了糖尿病引起的视网膜厚度下降、炎症和视力损害。小胶质细胞/巨噬细胞中的 Kdm6a 以去甲基酶活性依赖的方式调节 Lcn2 的表达，并通过 Lcn2 抑制光感受器细胞中的糖酵解进程。这些结果表明，小胶质细胞/巨噬细胞中的 Kdm6a 通过促进 Lcn2 的表达和损害光感受器细胞中的糖酵解进程加重了糖尿病性视网膜病变。
