A Single-Cell Transcriptome Profiling of Triptolide-Induced Nephrotoxicity in Mice

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-06-12 DOI:10.1002/adbi.202400120
Jiangpeng Wu, Jinan Guo, Siyu Xia, Jiayun Chen, Min Cao, Lulin Xie, Chuanbin Yang, Feng Qiu, Jigang Wang
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Abstract

Triptolide (TP), an active component isolated from the traditional Chinese herb Tripterygium wilfordii Hook F (TWHF), shows great promise for treating inflammation-related diseases. However, its potential nephrotoxic effects remain concerning. The mechanism underlying TP-induced nephrotoxicity is inadequately elucidated, particularly at single-cell resolution. Hence, single-cell RNA sequencing (scRNA-seq) of kidney tissues from control and TP-treated mice is performed to generate a thorough description of the renal cell atlas upon TP treatment. Heterogeneous responses of nephron epithelial cells are observed after TP exposure, attributing differential susceptibility of cell subtypes to excessive reactive oxygen species and increased inflammatory responses. Moreover, TP disrupts vascular function by activating endothelial cell immunity and damaging fibroblasts. Severe immune cell damage and the activation of pro-inflammatory Macro_C1 cells are also observed with TP treatment. Additionally, ligand-receptor crosstalk analysis reveals that the SPP1 (osteopontin) signaling pathway targeting Macro_C1 cells is triggered by TP treatment, which may promote the infiltration of Macro_C1 cells to exacerbate renal toxicity. Overall, this study provides comprehensive information on the transcriptomic profiles and cellular composition of TP-associated nephrotoxicity at single-cell resolution, which can strengthen the understanding of the pathogenesis of TP-induced nephrotoxicity and provide valuable clues for the discovery of new therapeutic targets to ameliorate TP-associated nephrotoxicity.

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小鼠单细胞转录组分析:雷公藤内酯诱发的肾毒性
雷公藤内酯(Triptolide,TP)是从传统中草药雷公藤(Tripterygium wilfordii Hook F,TWHF)中分离出来的一种活性成分,在治疗炎症相关疾病方面前景广阔。然而,其潜在的肾毒性作用仍令人担忧。TP诱导肾毒性的机制尚未得到充分阐明,尤其是在单细胞分辨率方面。因此,我们对对照组和 TP 治疗小鼠的肾组织进行了单细胞 RNA 测序(scRNA-seq),以全面描述 TP 治疗后的肾细胞图谱。观察到肾小球上皮细胞在暴露于 TP 后出现了不同的反应,这归因于细胞亚型对过量活性氧和炎症反应增加的敏感性不同。此外,TP 还可通过激活内皮细胞免疫和损伤成纤维细胞来破坏血管功能。经 TP 处理后,还可观察到严重的免疫细胞损伤和促炎 Macro_C1 细胞的活化。此外,配体-受体串扰分析表明,TP 治疗会触发靶向 Macro_C1 细胞的 SPP1(骨通蛋白)信号通路,这可能会促进 Macro_C1 细胞的浸润,从而加剧肾毒性。总之,本研究提供了单细胞分辨率的 TP 相关肾毒性转录组图谱和细胞组成的全面信息,可加强对 TP 诱导肾毒性发病机制的认识,并为发现新的治疗靶点以改善 TP 相关肾毒性提供有价值的线索。
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CiteScore
7.20
自引率
4.30%
发文量
567
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