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Updated: Jun 7, 2025
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4
Qianlei Wang1, Mengyang Li1, Fei Duan1
1Institute 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.
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.
Insights
G protein-coupled receptor kinase 2 (GRK2) drives cisplatin-induced acute liver injury (ALI) by increasing oxidative stress and endoplasmic reticulum stress. Inhibiting GRK2 protects against liver damage, suggesting GRK2 as a therapeutic target.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Acute liver injury (ALI) induced by cisplatin poses a significant clinical challenge.
- G protein-coupled receptor kinase 2 (GRK2) role in ALI pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of GRK2 in cisplatin-induced ALI.
- To evaluate the protective effects of pharmacological GRK2 inhibition in ALI.
Main Methods:
- Generated ALI models in hemizygous GRK2 (Grk2±) and wild-type (WT) mice.
- Assessed liver injury using biochemical parameters and histopathology.
- Utilized GRK2-siRNA and pharmacological inhibitors (CP-25, paroxetine) in vitro and in vivo.
Main Results:
- Cisplatin increased GRK2, p-GRK2, and NADPH oxidase 4 (NOX4) expression, leading to elevated AST/ALT, oxidative stress, ER stress, and apoptosis.
- Grk2± mice and GRK2 inhibition significantly reduced liver injury markers, NOX4 levels, ER stress, and apoptosis.
- In vitro studies confirmed GRK2 inhibition's protective effects against cisplatin-induced cellular damage.
Conclusions:
- GRK2 mediates cisplatin-induced ALI by modulating NOX4 and ER stress pathways.
- Pharmacological inhibition of GRK2 effectively alleviates liver injury.
- GRK2 represents a promising therapeutic target for preventing and treating liver injury.
