Necroptosis in renal ischemia/reperfusion injury: A major mode of cell death?

Ischemic acute kidney injury (AKI) is a frequent complication resulting from a myriad of conditions that decrease effective arterial blood volume to the kidneys including myocardial ischemia, sepsis, and hypovolemia. Following acute ischemic insult, restoration of renal blood flow inevitably leads to the aggravation of renal injury due to a widely researched condition known as ischemia/reperfusion (I/R) injury. For decades, apoptosis and necrosis have been proposed as being the two cell death pathways responsible for the pathogenesis of renal ischemic AKI. There is recent evidence to show that necrosis could be regulated in a caspase-independent manner. This regulated or programmed necrosis is termed necroptosis. Necroptotic markers such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain like pseudokinase (MLKL) have been identified in both in vitro and in vivo models of renal I/R injury, suggesting that necroptosis might be a potential therapeutic target to limit renal I/R injury. In this review, available reports from in vitro, in vivo and clinical reports regarding the association of necroptosis in renal I/R injury, along with its therapeutic potential, has been comprehensively summarized and discussed. Understanding this contributory mechanism could pave ways to improve therapeutic strategies in combating renal I/R injury.