Bai Yunfeng, Chi Kun, Zhao Delong, Shen Wanjun, Liu Ran, Hao Jing, Cai Guangyan, Chen Xiangmei, Hong Quan
Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.
J Transl Int Med. 2024 Oct 1;12(4):395-405. doi: 10.2478/jtim-2023-0130. eCollection 2024 Sep.
Renal inflammation plays key roles in the pathogenesis of diabetic kidney disease (DKD). Immune cell infiltration is the main pathological feature in the progression of DKD. Sodium glucose cotransporter 2 inhibitor (SGLT2i) were reported to have antiinflammatory effects on DKD. While the heterogeneity and molecular basis of the pathogenesis and treatment with SGLT2i in DKD remains poorly understood.
To address this question, we performed a single-cell transcriptomics data analysis and cell cross-talk analysis based on the database (GSE181382). The single-cell transcriptome analysis findings were validated using multiplex immunostaining.
A total of 58760 cells are categorized into 25 distinct cell types. A subset of macrophages with anti-inflammatory potential was identified. We found that Ccl3+ (S100a8/a9 high) macrophages with anti-inflammatory and antimicrobial in the pathogenesis of DKD decreased and reversed the dapagliflozin treatment. Besides, dapagliflozin treatment enhanced the accumulation of Pck1+ macrophage, characterized by gluconeogenesis signaling pathway. Cell-cross talk analysis showed the GRN/SORT1 pair and CD74 related signaling pathways were enriched in the interactions between tubular epithelial cells and immune cells.
Our study depicts the heterogeneity of macrophages and clarifies a new possible explanation of dapagliflozin treatment, showing the metabolism shifts toward gluconeogenesis in macrophages, fueling the anti-inflammatory function of M2 macrophages, highlighting the new molecular features and signaling pathways and potential therapeutic targets, which has provided an important reference for the study of immune-related mechanisms in the progression of the disease.
肾脏炎症在糖尿病肾病（DKD）的发病机制中起关键作用。免疫细胞浸润是DKD进展的主要病理特征。据报道，钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）对DKD具有抗炎作用。然而，DKD发病机制及SGLT2i治疗的异质性和分子基础仍知之甚少。
为解决这一问题，我们基于数据库（GSE181382）进行了单细胞转录组数据分析和细胞间相互作用分析。单细胞转录组分析结果通过多重免疫染色进行验证。
共将58760个细胞分为25种不同的细胞类型。鉴定出具有抗炎潜力的巨噬细胞亚群。我们发现，在DKD发病机制中具有抗炎和抗菌作用的Ccl3 +（S100a8/a9高）巨噬细胞减少，并且达格列净治疗可使其逆转。此外，达格列净治疗增强了Pck1 +巨噬细胞的积累，其特征为糖异生信号通路。细胞间相互作用分析显示，GRN/SORT1对和CD74相关信号通路在肾小管上皮细胞与免疫细胞之间的相互作用中富集。
我们的研究描绘了巨噬细胞的异质性，阐明了达格列净治疗的一种新的可能解释，表明巨噬细胞的代谢向糖异生转变，增强了M2巨噬细胞的抗炎功能，突出了新的分子特征和信号通路以及潜在的治疗靶点，为疾病进展中免疫相关机制的研究提供了重要参考。
