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

Cell Biol Toxicol. 2024 Nov 15;40(1):98. doi: 10.1007/s10565-024-09940-y.

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.

Keywords: Cisplatin; Endoplasmic reticulum stress; GRK2; Liver injury; NOX4.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cell Line
  • Chemical and Drug Induced Liver Injury* / metabolism
  • Cisplatin* / pharmacology
  • Disease Models, Animal
  • Endoplasmic Reticulum Chaperone BiP*
  • Endoplasmic Reticulum Stress* / drug effects
  • G-Protein-Coupled Receptor Kinase 2* / genetics
  • G-Protein-Coupled Receptor Kinase 2* / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase 4* / genetics
  • NADPH Oxidase 4* / metabolism
  • Oxidative Stress / drug effects

Substances

  • Cisplatin
  • NADPH Oxidase 4
  • G-Protein-Coupled Receptor Kinase 2
  • Endoplasmic Reticulum Chaperone BiP
  • Hspa5 protein, mouse
  • Nox4 protein, mouse
  • GRK2 protein, mouse