Kidney cell response to acute cardiorenal and isolated kidney ischemia-reperfusion injury.

IF 2.5 4区 生物学 Q3 CELL BIOLOGY
Physiological genomics Pub Date : 2025-04-01 Epub Date: 2025-02-21 DOI:10.1152/physiolgenomics.00161.2024
Kevin G Burfeind, Yoshio Funahashi, Xiao-Tong Su, Anne E Lackey, Matt W Hagen, Sienna Blanche, Jacqueline M Emathinger, Jessica F Hebert, Alicia A McDonough, Susan B Gurley, Jonathan W Nelson, Michael P Hutchens
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引用次数: 0

Abstract

Acute cardiorenal syndrome (CRS) represents a critical intersection of cardiac and renal dysfunction with profound clinical implications. Despite its significance, the molecular underpinnings that mediate cellular responses within the kidney during CRS remain inadequately understood. We used single nucleus RNA sequencing (snRNAseq) to dissect the cellular transcriptomic landscape of the kidney following a translational model of CRS, cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in comparison to ischemia-reperfusion injury (IRI). In each dataset, we found that proximal tubule (PT) cells of the kidney undergo significant gene expression changes, with decreased expression of genes critically important for cell identity and function, indicative of dedifferentiation. Based on this, we created a novel score to capture the dedifferentiation state of each kidney cell population and found that certain epithelial cell populations, such as the PT S1 and S2 segments, as well as the distal convoluted tubule, exhibited significant dedifferentiation response. Interestingly, the dedifferentiation response in the distal nephron differed in magnitude between IRI and CA/CPR. Gene set enrichment analysis (GSEA) of PT response to IRI and CA/CPR revealed similarities between the two models and key differences, including enrichment of immune system process genes. Transcriptional changes in both mouse models of acute kidney injury (AKI) highly correlated with a dataset of human biopsies from patients diagnosed with AKI. This comprehensive single-nucleus transcriptomic profiling provides valuable insights into the cellular mechanisms driving CRS.NEW & NOTEWORTHY Cardiac dysfunction is a common cause of acute kidney injury in a malady called acute cardiorenal syndrome. In a mouse model of acute cardiorenal syndrome called cardiac arrest/cardiopulmonary resuscitation, we characterized, for the first time, the kidney transcriptional landscape at the single-cell level. We developed a novel method for quantifying cell response to injury and found that cells adapted through dedifferentiation, the magnitude of which varied depending on cell type.

肾细胞对急性心肾和离体肾缺血再灌注损伤的反应。
急性心肾综合征(CRS)是心脏和肾脏功能障碍的一个重要交叉点,具有深远的临床意义。尽管其意义重大,但CRS期间肾脏内介导细胞反应的分子基础仍未充分了解。我们使用单核RNA测序(snRNAseq)来解剖CRS,心脏骤停/心肺复苏(CA/PCR)与缺血再灌注损伤(IRI)的翻译模型中肾脏的细胞转录组学景观。在每个数据集中,我们发现肾脏近端小管(PT)细胞经历了显著的基因表达变化,对细胞身份和功能至关重要的基因表达减少,表明去分化。在此基础上,我们创建了一个新的评分来捕捉每个肾细胞群的去分化状态,并发现某些上皮细胞群,如PT S1和S2段,以及远曲小管,表现出显著的去分化反应。有趣的是,IRI和CA/CPR对远端肾元的去分化反应的程度不同。PT对IRI和CA/CPR反应的基因集富集分析(GSEA)揭示了两种模型之间的相似性和关键差异,包括免疫系统过程基因的富集。两种AKI小鼠模型的转录变化与诊断为急性肾损伤(AKI)的患者的人类活检数据集高度相关。这种全面的单核转录组分析为驱动CRS的细胞机制提供了有价值的见解。
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
Physiological genomics
Physiological genomics 生物-生理学
CiteScore
6.10
自引率
0.00%
发文量
46
审稿时长
4-8 weeks
期刊介绍: The Physiological Genomics publishes original papers, reviews and rapid reports in a wide area of research focused on uncovering the links between genes and physiology at all levels of biological organization. Articles on topics ranging from single genes to the whole genome and their links to the physiology of humans, any model organism, organ, tissue or cell are welcome. Areas of interest include complex polygenic traits preferably of importance to human health and gene-function relationships of disease processes. Specifically, the Journal has dedicated Sections focused on genome-wide association studies (GWAS) to function, cardiovascular, renal, metabolic and neurological systems, exercise physiology, pharmacogenomics, clinical, translational and genomics for precision medicine, comparative and statistical genomics and databases. For further details on research themes covered within these Sections, please refer to the descriptions given under each Section.
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