Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

I Rubera,B Mograbi,C Duranton,M Cougnon,M Tauc,N Melis

doi:10.1038/cddis.2013.355

Abstract

The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl− channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTRinh-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTRinh-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTRinh-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTRinh-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTRinh-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.

Highlights

The pathogenesis of cisplatin-induced nephrotoxicity is complex and several mechanisms have been proposed to explain the cytotoxic effects of this drug in renal tubular cells
In contrast to BSO, the addition of a-tocopherol prevented cisplatin-induced cell death. These data suggest that cisplatin-induced cell death is largely mediated through an increase in the level of oxidative stress and that the inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) by CFTRinh-172 prevents the toxic effects of cisplatin in renal cells (Figures 1b and c)
In addition to its therapeutic cytotoxic effect on cancer cells through its ability to bind DNA, cisplatin has been reported to induce oxidative stress, which is damaging to the kidney, an organ that is highly vulnerable to the damage caused by reactive oxygen species (ROS)

Summary

Introduction

The pathogenesis of cisplatin-induced nephrotoxicity is complex and several mechanisms have been proposed to explain the cytotoxic effects of this drug in renal tubular cells. Both transporters have been implicated in cisplatin uptake and cytotoxicity in vitro[5,6] and in vivo.[7] Once inside the cells, cisplatin undergoes aquation and interacts with cellular components, such as DNA, inducing intrastrand and interstrand cross-linking.[1] Cisplatin causes tubular cell death by either apoptosis or necrosis, depending on the concentration and the exposure duration.[8] Numerous studies have described the different pathways implicated in cisplatininduced apoptosis;[3,9] among these pathways, mitochondrial dysfunction and oxidative stress appear to be important events in the induction of cisplatin toxicity.[10] Cisplatin-induced acute renal failure is associated with the generation of reactive oxygen species (ROS), lipid peroxidation and a decrease in antioxidant buffering systems, such as GSH.[10,11,12]. CFTR is a cAMP-dependent chloride channel and a modulator of other ion channels

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Conclusion