GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4.

IF 5.3 2区医学 Q2 CELL BIOLOGY Cell Biology and Toxicology Pub Date : 2024-11-15 DOI:10.1007/s10565-024-09940-y

Qianlei Wang, Mengyang Li, Fei Duan, Kangjun Xiao, Qing Qing Sun, Jiang Rui Cheng, Lei Ni, Zhengkun Xu, Bingfa Xu, Feng Xiao, Jiajie Kuai, Wei Wei, Chun Wang

{"title":"GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4.","authors":"Qianlei Wang, Mengyang Li, Fei Duan, Kangjun Xiao, Qing Qing Sun, Jiang Rui Cheng, Lei Ni, Zhengkun Xu, Bingfa Xu, Feng Xiao, Jiajie Kuai, Wei Wei, Chun Wang","doi":"10.1007/s10565-024-09940-y","DOIUrl":null,"url":null,"abstract":"Background: The present study investigated the function of G protein-coupled receptor kinase 2 (GRK2) in acute liver injury (ALI) by cisplatin, and investigated the protective effect of pharmacological inhibition of GRK2.Methods: ALI models were generated in global adult hemizygous (ALI-Grk2±) mice and wild-type (WT) mice. Liver biochemistry parameters and histopathology were used to evaluate the severity of ALI and the protective effect of pharmacological inhibition of GRK2. GRK2-siRNA was used to knock down the expression of GRK2 in AML12 cells in vitro.Results: ALI model mice exhibited increased blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver pathology accompanied by imbalanced L-glutathione (GSH) levels. Cisplatin administration upregulated GKR2, p-GRK2 and NADPH oxidase 4 (NOX4) expression in the liver tissues of ALI model mice. Compared to WT mice injected with cisplatin, Grk2± mice that received cisplatin showed significant improvements in liver function and pathological performance, decreased NOX4 levels, reduced endoplasmic reticulum (ER) stress, and diminished liver cell apoptosis. In vitro, the transfection of AML12 cells with siRNA significantly reduced NOX4 expression and inhibited cisplatin-induced reactive oxygen species production, ER stress (increased levels of GRP94, GRP78, p-elF2α and CHOP) and apoptotic death. Moreover, pharmacological treatment with drugs that inhibit GRK2 (CP-25 or paroxetine) significantly ameliorated cisplatin-induced ALI by improving liver pathological manifestations, inhibiting oxidative stress and ER stress, and reducing liver cell apoptosis. Similar results were observed in vitro.Conclusions: GRK2 mediates the development of cisplatin-induced ALI by modulating NOX4 and ER stress. Pharmacological inhibition of GRK2 with CP-25 or paroxetine effectively alleviated ALI. GRK2 can be used as a potential target for the prevention and treatment of liver injury.","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"98"},"PeriodicalIF":5.3000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567994/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Biology and Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10565-024-09940-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: The present study investigated the function of G protein-coupled receptor kinase 2 (GRK2) in acute liver injury (ALI) by cisplatin, and investigated the protective effect of pharmacological inhibition of GRK2.

Methods: ALI models were generated in global adult hemizygous (ALI-Grk2^±) mice and wild-type (WT) mice. Liver biochemistry parameters and histopathology were used to evaluate the severity of ALI and the protective effect of pharmacological inhibition of GRK2. GRK2-siRNA was used to knock down the expression of GRK2 in AML12 cells in vitro.

Results: ALI model mice exhibited increased blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver pathology accompanied by imbalanced L-glutathione (GSH) levels. Cisplatin administration upregulated GKR2, p-GRK2 and NADPH oxidase 4 (NOX4) expression in the liver tissues of ALI model mice. Compared to WT mice injected with cisplatin, Grk2^± mice that received cisplatin showed significant improvements in liver function and pathological performance, decreased NOX4 levels, reduced endoplasmic reticulum (ER) stress, and diminished liver cell apoptosis. In vitro, the transfection of AML12 cells with siRNA significantly reduced NOX4 expression and inhibited cisplatin-induced reactive oxygen species production, ER stress (increased levels of GRP94, GRP78, p-elF2α and CHOP) and apoptotic death. Moreover, pharmacological treatment with drugs that inhibit GRK2 (CP-25 or paroxetine) significantly ameliorated cisplatin-induced ALI by improving liver pathological manifestations, inhibiting oxidative stress and ER stress, and reducing liver cell apoptosis. Similar results were observed in vitro.

Conclusions: GRK2 mediates the development of cisplatin-induced ALI by modulating NOX4 and ER stress. Pharmacological inhibition of GRK2 with CP-25 or paroxetine effectively alleviated ALI. GRK2 can be used as a potential target for the prevention and treatment of liver injury.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

GRK2通过调节NOX4介导顺铂诱导的急性肝损伤

背景：本研究探讨了G蛋白偶联受体激酶2（GRK2）在顺铂引起的急性肝损伤（ALI）中的功能，并研究了药物抑制GRK2的保护作用：方法：在全球成年半杂合子（ALI-Grk2±）小鼠和野生型（WT）小鼠中建立ALI模型。用肝脏生化指标和组织病理学评估 ALI 的严重程度和药物抑制 GRK2 的保护作用。使用 GRK2-siRNA 在体外敲除 AML12 细胞中 GRK2 的表达：ALI模型小鼠血液中天门冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平升高，肝脏病理异常并伴有左旋谷胱甘肽（GSH）水平失衡。顺铂会上调 ALI 模型小鼠肝组织中 GKR2、p-GRK2 和 NADPH 氧化酶 4 (NOX4) 的表达。与注射顺铂的 WT 小鼠相比，接受顺铂治疗的 Grk2± 小鼠的肝功能和病理表现明显改善，NOX4 水平降低，内质网（ER）应激减少，肝细胞凋亡减少。在体外，用 siRNA 转染 AML12 细胞可明显降低 NOX4 的表达，抑制顺铂诱导的活性氧生成、ER 应激（GRP94、GRP78、p-elF2α 和 CHOP 水平升高）和细胞凋亡。此外，抑制 GRK2 的药物（CP-25 或帕罗西汀）通过改善肝脏病理表现、抑制氧化应激和 ER 应激以及减少肝细胞凋亡，显著改善了顺铂诱导的 ALI。在体外也观察到了类似的结果：结论：GRK2通过调节NOX4和ER应激介导顺铂诱导的ALI的发展。CP-25或帕罗西汀对GRK2的药理抑制可有效缓解ALI。GRK2可作为预防和治疗肝损伤的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

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.