AST-120 alleviates renal ischemia-reperfusion injury by inhibiting HK2-mediated glycolysis.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jinmeng Zhou, Jinbao Zhang, Feng Xu, Haijin Gao, Lei Wang, Yutong Zhao, Ke Li
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Abstract

Objective: Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which is associated with high incidence and mortality. AST-120 is an oral carbonaceous adsorbent that can alleviate kidney damage. This study aimed to explore the effects of AST-120 on renal IRI and the molecular mechanism.

Methods: A renal IRI mouse model was established and administrated AST-120, and differentially expressed genes were screened using RNA sequencing. Renal function and pathology were analyzed in mice. Hypoxia/reoxygenation (H/R) cell model was generated, and glycolysis was evaluated by detecting lactate levels and Seahorse analysis. Histone lactylation was analyzed by western blotting, and its relationship with hexokinase 2 (HK2) was assessed using chromatin immunoprecipitation.

Results: The results showed that HK2 expression was increased after IRI, and AST-120 decreased HK2 expression. Knockout of HK2 attenuated renal IRI and inhibits glycolysis. AST-120 inhibited renal IRI in the presence of HK2 rather than HK2 absence. In proximal tubular cells, knockdown of HK2 suppressed glycolysis and H3K18 lactylation caused by H/R. H3K18 lactylation was enriched in HK2 promoter and upregulated HK2 levels. Rescue experiments revealed that lactate reversed IRI that suppressed by HK2 knockdown.

Conclusions: In conclusion, AST-120 alleviates renal IRI via suppressing HK2-mediated glycolysis, which suppresses H3K18 lactylation and further reduces HK2 levels. This study proposes a novel mechanism by which AST-120 alleviates IRI.

AST-120 通过抑制 HK2- 介导的糖酵解减轻肾缺血再灌注损伤
目的:肾缺血再灌注损伤(IRI)是急性肾损伤(AKI)的主要原因,其发病率和死亡率都很高。AST-120 是一种口服碳质吸附剂,可减轻肾损伤。本研究旨在探讨 AST-120 对肾脏 IRI 的影响及其分子机制:方法:建立肾脏 IRI 小鼠模型并给予 AST-120,使用 RNA 测序筛选差异表达基因。对小鼠的肾功能和病理学进行分析。建立缺氧/复氧(H/R)细胞模型,通过检测乳酸水平和海马分析评估糖酵解。通过Western印迹分析了组蛋白乳酰化,并利用染色质免疫沉淀评估了组蛋白乳酰化与己糖激酶2(HK2)的关系:结果:结果显示,IRI后HK2表达增加,而AST-120会降低HK2的表达。敲除 HK2 可减轻肾脏 IRI 并抑制糖酵解。在有 HK2 的情况下,AST-120 可抑制肾脏 IRI,而在没有 HK2 的情况下,AST-120 则不能抑制肾脏 IRI。在近端肾小管细胞中,敲除HK2可抑制H/R引起的糖酵解和H3K18乳化。H3K18乳化富集在HK2启动子中,并上调了HK2的水平。拯救实验显示,乳酸逆转了被HK2敲除抑制的IRI:总之,AST-120通过抑制HK2-介导的糖酵解,从而抑制H3K18乳酸化并进一步降低HK2水平来缓解肾脏IRI。本研究提出了 AST-120 缓解 IRI 的新机制。
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
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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