Runt 相关转录因子 1 (RUNX1) 是急性肾损伤的介质。

IF 5.6 2区 医学 Q1 ONCOLOGY The Journal of Pathology Pub Date : 2024-10-29 DOI:10.1002/path.6355
Miguel Fontecha-Barriuso, Natalia Villar-Gomez, Juan Guerrero-Mauvecin, Julio M Martinez-Moreno, Susana Carrasco, Diego Martin-Sanchez, María Rodríguez-Laguna, Manuel J Gómez, María D Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz, Ana B Sanz
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引用次数: 0

摘要

急性肾损伤(AKI)的治疗效果并不理想。更好地了解 AKI 的发病机制可能会带来新的治疗方法。叶酸诱导的急性肾损伤(FA-AKI)小鼠肾脏转录组学发现,RUNX1是上调最多的RUNX家族基因。我们随后研究了RUNX1在叶酸诱导的AKI、细菌脂多糖(LPS)诱导的细胞因子风暴-AKI(CS-AKI)和人类AKI中的表达。在培养的小鼠肾小管细胞中,我们探讨了 RUNX1 在细胞因子 TWEAK 或 LPS 诱导的反应中的表达和作用。在 AKI 动物模型中使用了 RUNX1 化学抑制剂(Ro5-3335),以测试其作为治疗靶点的潜力。RUNX1在FA-AKI中的过表达在mRNA和蛋白质水平上得到了验证,并且主要定位于肾小管细胞核。CS-AKI 也上调了肾脏 RUNX1。在人类 AKI 中也观察到肾小管和肾间质 RUNX1 表达增加。在培养的小鼠肾小管细胞中,促炎细胞因子 TWEAK 和 LPS 增加了 RUNX1 和 IL-6 的表达。从机制上讲,RUNX1与Il6基因启动子结合,用化学抑制剂Ro5-3335或特异性小干扰RNA(siRNA)靶向RUNX1,可通过RUNX1/NFκB1 p50途径阻止TWEAK和LPS诱导的IL6上调。在体内,预防性 Ro5-3335 可改善 FA-AKI 和 CS-AKI 的肾功能并减轻炎症反应。然而,在损伤后服用Ro5-3335只能改善CS-AKI的肾功能。肾脏转录组学发现,炎症基因和转录因子 mRNA(如 Yap1 和 Trp53)是 Ro5-3335 在 CS-AKI 中的关键靶点。总之,RUNX1通过驱动炎症相关基因的表达促进了AKI,是AKI的一个新的治疗靶点。© 2024 作者。病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。
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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Runt-related transcription factor 1 (RUNX1) is a mediator of acute kidney injury

Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of the pathogenesis of AKI may lead to new therapeutic approaches. Kidney transcriptomics of folic acid-induced AKI (FA-AKI) in mice identified Runx1 as the most upregulated RUNX family gene. We then examined the expression of RUNX1 in FA-AKI, in bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI (CS-AKI), and in human AKI. In cultured mouse tubule cells, we explored the expression and role of RUNX1 in response to the cytokine TWEAK or LPS. A chemical inhibitor of RUNX1 (Ro5-3335) was used in animal models of AKI to test its potential as a therapeutic target. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubule cell nuclei. CS-AKI also upregulated kidney RUNX1. Increased tubule and interstitial RUNX1 expression were also observed in human AKI. In cultured mouse tubule cells, the pro-inflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il6 gene promoter and RUNX1 targeting with the chemical inhibitor Ro5-3335, or a specific small interfering RNA (siRNA), prevented the TWEAK- and LPS-induced upregulation of IL6 through a RUNX1/NFκB1 p50 pathway. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation in FA-AKI and CS-AKI. However, Ro5-3335 administration after the insult only improved kidney function in CS-AKI. Kidney transcriptomics identified inflammatory genes and transcription factor mRNAs such as Yap1 and Trp53 as key targets of Ro5-3335 in CS-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
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