Mechanisms of Cisplatin nephrotoxicity

Abstract

Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.

Keywords: apoptosis; cisplatin; cytokines; dendritic cells; inflammation; kidney injury; nephrotoxicity; toll-like receptors.

Figure 1

Pathways of cisplatin-induced epithelial cell death. Cisplatin enters renal epithelial cells via the OCT2 and, to a lesser extent, Ctr1 transporters. Cisplatin causes damage to nuclear and mitochondrial DNA and production of reactive oxygen species (ROS) which lead to activation of both mitochondrial and non-mitochondrial pathways of apoptosis and necrosis.

Figure 2

Immune mechanisms of cisplatin nephrotoxicity. Cisplatin-induced injury to renal epithelial cells causes release of DAMPs, which activate TLR4. Activation of TLR4 results in the production of a variety of chemokines and cytokines, including TNF-α. These chemokines and cytokines upregulate adhesion molecules and attract inflammatory cells, such as neutrophils and T cells, into the region of injury. Tissue resident dendritic cells act to reduce kidney injury, at least in part by producing the anti-inflammatory cytokine IL-10. Treg cells also reduce kidney injury although the mechanism is still unknown. Dendritic cells may enhance the number or activity of Treg cells, though this has not been demonstrated.