Xiong Sheng-Xi, Huang Lin-Juan, Liu Han-Shuang, Zhang Xiao-Xiao, Li Min, Cui Yu-Bing, Shao Chen, Hu Xiao-Lei
Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China.
Department of Endocrinology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China.
World J Diabetes. 2025 Feb 15;16(2):97287. doi: 10.4239/wjd.v16.i2.97287.
Macrophages are central to the orchestration of immune responses, inflammatory processes, and the pathogenesis of diabetic complications. The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy. Sodium-glucose cotransporter 2 inhibitors such as dapagliflozin, which are acclaimed for their efficacy in diabetes management, may influence macrophage polarization, thereby ameliorating diabetic nephropathy. This investigation delves into these mechanistic pathways, aiming to elucidate novel therapeutic strategies for diabetes.
To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action.
We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin. Concurrently, the human monocyte cell line cells were used for studies. Macrophage viability was assessed in a cell counting kit 8 assay, whereas apoptosis was evaluated by Annexin V/propidium iodide staining. Protein expression was examined through western blotting, and the expression levels of macrophage M1 surface markers, inflammatory cytokines, and apoptotic factors were quantified using flow cytometry, enzyme linked immunosorbent assay, and quantitative real-time polymerase chain reaction analyses.
Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice, evidenced by the downregulation of proapoptotic genes (), inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-α, and IL-1β], and M1 surface markers (inducible nitric oxide synthase, and cluster of differentiation 86), as well as the upregulation of the antiapoptotic gene . Moreover, dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway (PI3K, AKT, phosphorylated protein kinase B). These observations were corroborated , where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P, an activator of the PI3K/AKT signaling pathway.
Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype, thereby mitigating inflammation and promoting macrophage apoptosis. These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.
巨噬细胞在免疫反应、炎症过程及糖尿病并发症的发病机制中起核心作用。巨噬细胞向M1和M2表型的动态极化对炎症起着关键调节作用，并促进糖尿病肾病的进展。钠-葡萄糖协同转运蛋白2抑制剂（如达格列净）因其在糖尿病管理中的疗效而备受赞誉，可能会影响巨噬细胞极化，从而改善糖尿病肾病。本研究深入探讨这些作用机制途径，旨在阐明糖尿病的新型治疗策略。
研究达格列净对巨噬细胞M1极化和凋亡的抑制作用，并探讨其作用机制。
我们建立了2型糖尿病小鼠模型，并在给予达格列净治疗后收集腹腔巨噬细胞。同时，用人单核细胞系细胞进行研究。采用细胞计数试剂盒8法评估巨噬细胞活力，通过膜联蛋白V/碘化丙啶染色评估细胞凋亡。通过蛋白质免疫印迹法检测蛋白质表达，并使用流式细胞术、酶联免疫吸附测定和定量实时聚合酶链反应分析来定量巨噬细胞M1表面标志物、炎性细胞因子和凋亡因子的表达水平。
达格列净减弱了糖尿病小鼠腹腔巨噬细胞的M1极化并减轻了细胞凋亡，这表现为促凋亡基因、炎性细胞因子[白细胞介素（IL）-6、肿瘤坏死因子-α和IL-1β]以及M1表面标志物（诱导型一氧化氮合酶和分化簇86）的下调，以及抗凋亡基因的上调。此外，达格列净抑制了与磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路相关的蛋白质（PI3K、AKT、磷酸化蛋白激酶B）的表达。这些观察结果得到了证实，我们发现PI3K/AKT信号通路激活剂740Y-P消除了达格列净的调节作用。
达格列净减弱巨噬细胞向M1表型的极化，从而减轻炎症并促进巨噬细胞凋亡。这些作用可能是通过抑制PI3K/AKT信号通路介导的。
