Pharmacologically Inhibiting Glycogen Synthase Kinase-3β Ameliorates Renal Inflammation and Nephrotoxicity in an Animal Model of Cisplatin-Induced Acute Kidney Injury

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

doi:10.3390/biomedicines9080887

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.

Highlights

Cisplatin, a highly effective chemotherapeutic drug, is widely used to treat various cancers, including sarcomas, lymphomas, small-cell lung cancer, head and neck cancer, ovarian cancer, and testicular cancer [1]
Cisplatin Treatment Causes glycogen synthase kinase (GSK)-3β Activation Accompanied by Nephrotoxicity in an Experimental Murine Model of acute kidney injury (AKI)
Immunohistochemical staining showed that cisplatin induced GSK-3β activation, as

Summary

Introduction

A highly effective chemotherapeutic drug, is widely used to treat various cancers, including sarcomas, lymphomas, small-cell lung cancer, head and neck cancer, ovarian cancer, and testicular cancer [1]. Biomedicines 2021, 9, 887 cells and can cross-link with DNA to disrupt the double-helical structure of DNA [2]. Cisplatin can induce mitochondrial damage, cell cycle arrest, and cell death [3]. Regarding its cytotoxicity to normal tissues, nephrotoxicity is a major side effect that limits cisplatin treatment. Cisplatin induces renal tubular cell death, which leads to nephrotoxicity [3,4,5]

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Results

Conclusion