Kidney disease is poorly understood because of the organ’s cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.

由于器官的细胞多样性，人们对肾脏疾病知之甚少。我们不仅使用单细胞 RNA 测序来解决受损肾组织细胞组成的差异，而且还解决肾脏疾病小鼠模型中细胞类型特异性基因表达的差异。该分析强调了肾脏疾病中细胞多样性的重大变化，这显着影响了全肾转录组学输出。细胞类型特异性差异表达分析将近端小管 (PT) 细胞确定为关键的易受攻击的细胞类型。通过无偏见的细胞轨迹分析，我们表明 PT 细胞分化在肾脏疾病中发生了改变。PT 细胞中的代谢（脂肪酸氧化和氧化磷酸化）显示出与 PT 细胞分化和疾病的最强和最可重复的关联。