Single-nuclear transcriptomics reveals a diversity of proximal tubule cell states in a dynamic response to acute kidney injury.

We performed a mild-to-moderate ischemia reperfusion injury (IRI) to model injury responses reflective of kidney injury in a variety of clinical settings. Single-nuclear RNA-sequencing (snRNA-seq) of genetically labeled injured PTCs at 7-days (“early”) and 28-days (“late”) time points post-IRI identified specific gene and pathway activity in the injury-repair transition. In particular, we identified Vcam1+/Ccl2+ proximal tubule cells at a late injury stage distinguished by marked activation of NF-kB-, TNF- and AP-1-signaling pathways. This population of PTCs showed features of a senescence-associated secretory phenotype but did not exhibit G2/M cell cycle arrest. These pro-inflammatory, pro-fibrotic proximal tubule cells are likely triggers for chronic disease progression.

本研究构建轻中度缺血再灌注损伤（ischemia reperfusion injury, IRI）模型，以模拟多种临床场景下的肾脏损伤应答。随后，本研究对经基因标记的损伤性近端肾小管上皮细胞（proximal tubule cells, PTCs）在缺血再灌注损伤后7天("早期")与28天("晚期")两个时间点开展单核RNA测序（single-nuclear RNA-sequencing, snRNA-seq），鉴定出损伤修复过渡阶段的特异性基因与通路活性特征。尤为关键的是，本研究在损伤晚期阶段鉴定出Vcam1+/Ccl2+阳性近端肾小管上皮细胞群，该细胞群以核因子κB（nuclear factor kappa-B, NF-κB）、肿瘤坏死因子（tumor necrosis factor, TNF）以及激活蛋白1（activator protein 1, AP-1）信号通路的显著激活为特征。该群PTCs展现出衰老相关分泌表型（senescence-associated secretory phenotype, SASP）的相关特征，但未出现G2/M期细胞周期阻滞。这类促炎、促纤维化的近端肾小管上皮细胞极有可能成为慢性疾病进展的触发因素。

搜集汇总

背景与挑战

背景概述

该数据集通过小鼠肾脏的单核RNA测序，研究了急性肾损伤后近端肾小管细胞的动态响应。它揭示了在损伤后7天和28天的时间点，细胞状态多样性和特定基因通路活动，并识别出一个具有促炎、促纤维化特征的晚期损伤细胞群，有助于理解慢性肾病进展的潜在触发机制。