Pharmacologically inhibiting glycogen synthase kinase-3β ameliorates renal inflammation and nephrotoxicity in an animal model of cisplatin-induced acute kidney injury

Chung Hsi Hsing, Cheng Chieh Tsai, Chia Ling Chen, Yu Hui Lin, Po Chun Tseng, Rahmat Dani Satria, Chiou Feng Lin

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The adverse effect of cisplatin administration causes acute kidney injury (AKI) following renal inflammation and nephrotoxicity, characterized by proximal tubular cell apoptosis and necrosis. Pro-apoptotic and pro-inflammatory roles of glycogen synthase kinase (GSK)-3β have been reported. This study investigated the therapeutic blockade of GSK-3β in cisplatin-induced AKI. A renal cisplatin nephrotoxicity model showed activation of GSK-3β in vivo, particularly in proximal tubular epithelial cells. Pharmacologically inhibiting GSK-3β abolished cisplatin nephrotoxicity, including proximal tubular injury, cell cytotoxicity, and biochemical dysfunction. Additionally, GSK-3β inhibitor treatment ameliorated renal inflammation by reducing immune cell infiltration, cell adhesion molecule expression, and pro-inflammatory cytokine/chemokine production. Cisplatin treatment caused GSK-3β activation in vitro in the human renal proximal tubular epithelial cell line HK-2, whereas either pharmacological administration of GSK-3β inhibitors or genetic transduction of GSK-3β short-hairpin RNA impeded cisplatin-induced cytotoxicity. These results indicate that cisplatin activates GSK-3β followed by GSK-3β-mediated renal inflammation and nephrotoxicity, contributing to AKI.

Original languageEnglish
Article number887
JournalBiomedicines
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 2021

Keywords

  • AKI
  • Cisplatin
  • GSK-3β
  • Nephrotoxicity
  • Renal inflammation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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