Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity

Abstract

Background: Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury (AKI) which develop due to renal accumulation and biotransformation of CDDP. The alleviation or prevention of CDDP-caused nephrotoxicity is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis which is considered for high-dose CDDP-treated patients. However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical use of safe and efficacious renoprotective drug as an additive therapy for high dose CDDP-treated patients.

Main body: In this review article we describe in detail signaling pathways involved in CDDP-induced apoptosis of renal tubular cells, oxidative stress and inflammatory response in injured kidneys in order to pave the way for the design of new therapeutic approaches that can minimize CDDP-induced nephrotoxicity. Most of these molecular pathways are, at the same time, crucially involved in cytotoxic activity of CDDP against tumor cells and potential alterations in their function might mitigate CDDP-induced anti-tumor effects.

Conclusion: Despite the fact that many molecules were designated as potential therapeutic targets for renoprotection against CDDP, modulation of CDDP-induced nephrotoxicity still represents a balance on the knife edge between renoprotection and tumor toxicity.

Keywords: Acute kidney injury; Apoptosis; Cisplatin; Inflammation; Nephrotoxicity.

Fig. 1

P53 signaling pathways leading to tubular cell apoptosis after cisplatin treatment. By transcriptional regulation, nuclear p53 may activate proapoptotic genes, such as PUMA-α, caspases, PIDD, and ER-iPLA2, may suppress antiapoptotic genes, including p21 and TauT. In the absence of transcription, p53 may induce apoptosis via interactions with Bcl-2 family proteins in mitochondria and/or cytosol. Abbreviations: Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma-extra large; Bax: Bcl-2-associated X protein; Bak: Bcl-2 homologous antagonist killer; PUMA-α: p53 upregulated modulator of apoptosis; PIDD: p53-induced protein with a death domain; ER-iPLA2: Ca2⁺-independent phospholipase A2; Cdk2: Cyclin-dependent kinase complex; TauT: taurine transporter

Fig. 2

Cell subtypes that play crucial role in the pathogenesis of cisplatin-induced AKI. Cisplatin-induced AKI involves the coordinated actions of proximal tubular epithelial, endothelial, innate and adaptive immune cells. Abbreviations: ROS: Reactive oxygen species; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; MIF: Macrophage migration inhibitory factor; Mincle: Macrophage-inducible C-type lectin; CXCL1: Chemokine (C-X-C motif) ligand 1; Kim-1: Kidney injury molecule-1; ICAM-1: Intercellular adhesion molecule-1