GRK2 通过调节 NOX4 介导电离铂诱导的急性肝损伤。
GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4.
机构信息
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China.
Department of Pharmacy, the Third Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
出版信息
Cell Biol Toxicol. 2024 Nov 15;40(1):98. doi: 10.1007/s10565-024-09940-y.
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.
背景
本研究通过顺铂探讨了 G 蛋白偶联受体激酶 2（GRK2）在急性肝损伤（ALI）中的作用，并研究了抑制 GRK2 的药理作用的保护效果。
方法
在整体成年半合子（ALI-Grk2）小鼠和野生型（WT）小鼠中生成 ALI 模型。采用肝生化参数和组织病理学评估 ALI 的严重程度以及抑制 GRK2 的药理作用的保护效果。体外使用 GRK2-siRNA 敲低 AML12 细胞中 GRK2 的表达。
结果
ALI 模型小鼠表现出血清中天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平升高和异常的肝病理，同时伴有 L-谷胱甘肽（GSH）水平失衡。顺铂给药后，ALI 模型小鼠肝组织中 GRKR2、p-GRK2 和 NADPH 氧化酶 4（NOX4）表达上调。与注射顺铂的 WT 小鼠相比，接受顺铂的 Grk2 小鼠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。体外，AML12 细胞的 siRNA 转染显著降低了 NOX4 的表达并抑制了顺铂诱导的活性氧产生、ER 应激（GRP94、GRP78、p-elF2α 和 CHOP 水平升高）和凋亡死亡。此外，用抑制 GRK2 的药物（CP-25 或帕罗西汀）进行药理治疗通过改善肝病理表现、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。在体外也观察到了相似的结果。
结论
GRK2 通过调节 NOX4 和 ER 应激介导顺铂诱导的 ALI 的发生。CP-25 或帕罗西汀抑制 GRK2 可有效缓解 ALI。GRK2 可作为预防和治疗肝损伤的潜在靶点。
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