Yang Tongyue, Feng Qi, Shao Mingwei, Pan Mengxing, Guo Feng, Song Yi, Huang Fengjuan, Linlin Zhao, Wang Jiao, Wu Lina, Qin Guijun, Zhao Yanyan
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Pharmacol. 2024 Jul 17;15:1379821. doi: 10.3389/fphar.2024.1379821. eCollection 2024.
Diabetic kidney disease (DKD) is characterized by complex pathogenesis and poor prognosis; therefore, an exploration of novel etiological factors may be beneficial. Despite glycemic control, the persistence of transient hyperglycemia still induces vascular complications due to metabolic memory. However, its contribution to DKD remains unclear. Using single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, we clustered 12 cell types and employed enrichment analysis and a cell‒cell communication network. Fibrosis, a characteristic of DKD, was found to be associated with metabolic memory. To further identify genes related to metabolic memory and fibrosis in DKD, we combined the above datasets from humans with a rat renal fibrosis model and mouse models of metabolic memory. After overlapping, NDRG1, NR4A1, KCNC4 and ZFP36 were selected. Pharmacology analysis and molecular docking revealed that pioglitazone and resveratrol were possible agents affecting these hub genes. Based on the results, NDRG1 was selected for further study. Knockdown of NDRG1 reduced TGF-β expression in human kidney-2 cells (HK-2 cells). Compared to that in patients who had diabetes for more than 10 years but not DKD, NDRG1 expression in blood samples was upregulated in DKD patients. In summary, NDRG1 is a key gene involved in regulating fibrosis in DKD from a metabolic memory perspective. Bioinformatics analysis combined with experimental validation provided reliable evidence for identifying metabolic memory in DKD patients.
糖尿病肾病（DKD）具有发病机制复杂、预后不良的特点；因此，探索新的病因可能会有所帮助。尽管进行了血糖控制，但短暂高血糖的持续存在仍会因代谢记忆而诱发血管并发症。然而，其对DKD的作用仍不清楚。利用来自基因表达综合数据库（GEO）的单细胞RNA测序数据，我们对12种细胞类型进行了聚类，并进行了富集分析和细胞间通讯网络分析。纤维化是DKD的一个特征，发现其与代谢记忆有关。为了进一步确定DKD中与代谢记忆和纤维化相关的基因，我们将上述人类数据集与大鼠肾纤维化模型和代谢记忆小鼠模型相结合。经过重叠分析，选择了NDRG1、NR4A1、KCNC4和ZFP36。药理学分析和分子对接表明，吡格列酮和白藜芦醇可能是影响这些核心基因的药物。基于这些结果，选择NDRG1进行进一步研究。敲低NDRG1可降低人肾-2细胞（HK-2细胞）中转化生长因子-β（TGF-β）的表达。与患有糖尿病10年以上但无DKD的患者相比，DKD患者血样中的NDRG1表达上调。总之，从代谢记忆的角度来看，NDRG1是参与调节DKD纤维化的关键基因。生物信息学分析与实验验证相结合，为识别DKD患者的代谢记忆提供了可靠的证据。
