Activation of M1 macrophages promotes diabetic kidney disease by modulating glycolysis via HIF-1α-HK2 signaling pathway

作者：Xiaoyan Pei, Lijuan Lu, Ziqiong Huang, Wei Yu, Yu Li, Qiong Wang, Yanli Yang, Langen Zhuang, Guoxi Jin · 发表于：Diabetology & Metabolic Syndrome · 年份：2025 · DOI：10.1186/s13098-025-01894-3 · 被引用次数：14 · 研究领域：Immune cells in cancer、Chronic Kidney Disease and Diabetes、Dialysis and Renal Disease Management

OBJECTIVE: Macrophages and glycolysis play a pivotal role in diabetic kidney disease (DKD). However, the regulation of macrophage glycolysis and its mechanism are still unclear in DKD. Thus, this research intends to investigate the regulatory mechanism of macrophage glycolysis during DKD. METHODS: Macrophage polarization in patients with DKD and in mice was assessed using RT-qPCR and immunofluorescence. DKD was induced in the mice through injection of streptozotocin, and a high-fat diet was administered. Hematoxylin and eosin staining and Masson's trichrome staining were employed to identify pathological alterations and visualize renal collagen fibers in the model mice. Glycolytic metabolite levels were quantified using a commercially available kit. Protein levels of HK2, PFK1, LDH, PK1, and GLUT1 were analyzed via western blotting. Hkb-20 cells exposed to high glucose were utilized as an in vitro experimental model. THP-1 cells were co-cultivated with Hkb-20 cells. The impact of macrophage polarization on the functionality of Hkb-20 cells was assessed through CCK8 assay, flow cytometry, and wound healing assay. Levels of IL-6, IL-1β, and TNF-α were evaluated using ELISA kits. Immunofluorescence staining was employed to examine the co-localization of hypoxia-inducible factor-1 (HIF-1α) and HK2. RESULTS: We found that M1 macrophage polarization and enhanced glycolysis activity emerged in DKD patients and mice. Furthermore, we demonstrated that M1 macrophage polarization promot...