Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
Int J Mol Sci. 2023 Aug 31;24(17):13502. doi: 10.3390/ijms241713502.
Diabetic kidney disease (DKD) is one of the common chronic microvascular complications of diabetes in which mitochondrial disorder plays an important role in its pathogenesis. The current study delved into the single-cell level transcriptome heterogeneity of mitochondrial homeostasis in db/db mice, an animal model for study of type 2 diabetes and DKD, with single-cell RNA sequencing (scRNA-Seq) and bulk RNA-seq analyses. From the comprehensive dataset comprising 13 meticulously captured and authenticated renal cell types, an unsupervised cluster analysis of mitochondria-related genes within the descending loop of Henle, collecting duct principal cell, endothelial, B cells and macrophage, showed that they had two types of cell subsets, i.e., health-dominant and DKD-dominant clusters. Pseudotime analysis, cell communication and transcription factors forecast resulted in identification of the hub differentially expressed genes between these two clusters and unveiled that the hierarchical regulatory network of receptor-TF-target genes was triggered by mitochondrial degeneration. Furthermore, the collecting duct principal cells were found to be regulated by the decline of , which contributed to the impaired cellular proliferation and development, apoptosis and inactive cell cycle, as well as diminished capacity for material transport. Thereby, both scRNA-Seq and bulk RNA-Seq data from the current study elucidate the heterogeneity of mitochondrial disorders among distinct cell types, particularly in the collecting duct principal cells and B cells during the DKD progression and drug administration, which provide novel insights for better understanding the pathogenesis of DKD.
糖尿病肾病（DKD）是糖尿病常见的慢性微血管并发症之一，其中线粒体紊乱在其发病机制中起着重要作用。本研究通过单细胞 RNA 测序（scRNA-Seq）和批量 RNA-seq 分析，深入研究了 2 型糖尿病和 DKD 动物模型 db/db 小鼠线粒体稳态的单细胞水平转录组异质性。从包括 13 个精心捕获和鉴定的肾细胞类型的综合数据集，对 Henle 降支、收集管主细胞、内皮细胞、B 细胞和巨噬细胞中与线粒体相关的基因进行无监督聚类分析，表明它们有两种类型的细胞亚群，即健康主导和 DKD 主导集群。假时间分析、细胞通讯和转录因子预测导致鉴定出这两个簇之间的枢纽差异表达基因，并揭示了受体-TF-靶基因的层次调节网络是由线粒体退化触发的。此外，发现收集管主细胞受 的下降调节，这导致细胞增殖和发育受损、细胞凋亡和细胞周期不活跃，以及物质转运能力下降。因此，本研究的 scRNA-Seq 和批量 RNA-Seq 数据阐明了不同细胞类型中线粒体紊乱的异质性，特别是在 DKD 进展和药物治疗期间的收集管主细胞和 B 细胞中，为更好地理解 DKD 的发病机制提供了新的见解。
