Cell death induced by acute kidney injury: A perspective on the contributions of accidental and programmed cell death.

Abstract

The involvement of cell death in AKI is linked to multiple factors including nucleotide depletion, electrolyte imbalance, reactive oxygen species, endonucleases, disturbance of mitochondrial integrity, and activation of several cell death pathway components. Since our review in 2003, discussing the relative contributions of apoptosis and necrosis, several other forms of cell death have been identified and are shown to contribute to acute kidney injury (AKI). Currently, these various forms of cell death can be fundamentally divided into accidental cell death (ACD) and regulated or programmed cell death (RCD/PCD) based on functional aspects. Several death initiator and effector molecules, switch molecules that may act as signaling components triggering either death or protective mechanisms or alternate cell death pathways have been identified as part of the machinery. Intriguingly, several of these cell death pathways share components and signaling pathways suggesting complementary or compensatory functions. Thus defining the crosstalk between distinct cell death pathways and identifying the unique molecular effectors for each type of cell death may be required to develop novel strategies to prevent cell death. Further, depending on the multiple forms of cell death simultaneously induced in different AKI settings, strategies for combination therapies that block multiple cell death pathways need to be developed to completely prevent injury, cell death and renal function. This review highlights the various cell death pathways, crosstalk and interactions between different cell death modalities in AKI.