Spatio-temporal transcriptomic analysis reveals distinct nephrotoxicity, DNA damage, and regeneration response after cisplatin.

IF 5.9 2区 医学 Q2 CELL BIOLOGY
Lukas S Wijaya, Steven J Kunnen, Panuwat Trairatphisan, Ciarán P Fisher, Meredith E Crosby, Kai Schaefer, Karen Bodié, Erin E Vaughan, Laura Breidenbach, Thomas Reich, Diana Clausznitzer, Sylvestre Bonnet, Sipeng Zheng, Chantal Pont, James L Stevens, Sylvia E Le Dévédec, Bob van de Water
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Abstract

Nephrotoxicity caused by drug or chemical exposure involves complex mechanisms as well as a temporal integration of injury and repair responses in different nephron segments. Distinct cellular transcriptional programs regulate the time-dependent tissue injury and regeneration responses. Whole kidney transcriptome analysis cannot dissect the complex spatio-temporal injury and regeneration responses in the different nephron segments. Here, we used laser capture microdissection of formalin-fixed paraffin embedded sections followed by whole genome targeted RNA-sequencing-TempO-Seq and co-expression gene-network (module) analysis to determine the spatial-temporal responses in rat kidney glomeruli (GM), cortical proximal tubules (CPT) and outer-medulla proximal tubules (OMPT) comparison with whole kidney, after a single dose of the nephrotoxicant cisplatin. We demonstrate that cisplatin induced early onset of DNA damage in both CPT and OMPT, but not GM. Sustained DNA damage response was strongest in OMPT coinciding with OMPT specific inflammatory signaling, actin cytoskeletal remodeling and increased glycolytic metabolism with suppression of mitochondrial activity. Later responses reflected regeneration-related cell cycle pathway activation and ribosomal biogenesis in the injured OMPT regions. Activation of modules containing kidney injury biomarkers was strongest in OMPT, with OMPT Clu expression highly correlating with urinary clusterin biomarker measurements compared the correlation of Kim1. Our findings also showed that whole kidney responses were less sensitive than OMPT. In conclusion, our LCM-TempO-Seq method reveals a detailed spatial mechanistic understanding of renal injury/regeneration after nephrotoxicant exposure and identifies the most representative mechanism-based nephron segment specific renal injury biomarkers.

时空转录组学分析揭示了顺铂后不同的肾毒性、DNA损伤和再生反应。
药物或化学物质暴露引起的肾毒性涉及复杂的机制以及不同肾单元段损伤和修复反应的时间整合。不同的细胞转录程序调节时间依赖性组织损伤和再生反应。全肾转录组分析不能解剖复杂的时空损伤和不同肾元段的再生反应。在这里,我们使用激光捕获显微解剖福尔马林固定石蜡包埋切片,然后进行全基因组靶向rna测序-tempo -seq和共表达基因网络(模块)分析,以确定单剂量肾毒性顺铂后大鼠肾小球(GM),皮质近端小管(CPT)和外髓质近端小管(OMPT)与全肾的时空反应。我们证明,顺铂诱导CPT和OMPT的早期DNA损伤,但不诱导GM。OMPT的持续DNA损伤反应最强,与OMPT特异性炎症信号、肌动蛋白细胞骨架重塑和糖酵解代谢增加以及线粒体活性抑制相一致。随后的反应反映了损伤OMPT区域再生相关的细胞周期通路激活和核糖体生物发生。含有肾损伤生物标志物的模块在OMPT中激活最强,与Kim1的相关性相比,OMPT Clu表达与尿簇蛋白生物标志物测量高度相关。我们的研究结果还表明,全肾反应比OMPT更不敏感。总之,我们的LCM-TempO-Seq方法揭示了肾毒物暴露后肾损伤/再生的详细空间机制,并确定了最具代表性的基于机制的肾单元段特异性肾损伤生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Biology and Toxicology
Cell Biology and Toxicology 生物-毒理学
CiteScore
9.90
自引率
4.90%
发文量
101
审稿时长
>12 weeks
期刊介绍: Cell Biology and Toxicology (CBT) is an international journal focused on clinical and translational research with an emphasis on molecular and cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular pharmacology and toxicology. CBT has a disease-specific scope prioritizing publications on gene and protein-based regulation, intracellular signaling pathway dysfunction, cell type-specific function, and systems in biomedicine in drug discovery and development. CBT publishes original articles with outstanding, innovative and significant findings, important reviews on recent research advances and issues of high current interest, opinion articles of leading edge science, and rapid communication or reports, on molecular mechanisms and therapies in diseases.
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