Necroptosis in Acute Kidney Injury

Abstract

Background/Aims: Regulated necrosis is an expanding research field with important implications for acute kidney injury (AKI). A focused review of the evolving evidence for necroptosis in AKI, one of several forms of regulated necrosis defines the known and unknown. Methods: A literature search was performed in PUBMED and ScienceDirect between January 1957 and April 2018 using the following keywords: “acute kidney injury,” “necrosis,” “necroptosis,” “necroinflammation.” Results: The necroptosis signaling cascade involves a number of proteins including receptor-interacting protein-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL) as well as the MLKL regulator RGMb. The existing experimental evidence in AKI based on mice with genetic deletions of these proteins, more or less specific inhibitory compounds, and diverse experimental AKI models is reviewed. Conclusion: There is broad consistency suggesting a role for necroptosis in AKI, but some studies report divergent evidence potentially relating to the specific model used and the time point of analysis. Mlkl-deficient mice are currently the most specific and reliable experimental tool to study necroptosis in vivo (in kidney disease). The clinical potential of necroptosis inhibition in AKI is to be evaluated, but conceptual problems in AKI definitions and in complex clinical scenarios remain a concern.

Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

“…Necroptosis is a programmed form of necrosis and plays an essential role in AKI [34]. RIPK1, RPK3, and MLKL are key players in the process of necroptosis.…”

“…RIPK1, RPK3, and MLKL are key players in the process of necroptosis. Upon induction of necrosis, RIPK1 binds to RIPK3 and forms a multi-protein complex, leading to the phosphorylation and oligomerization of MLKL [34]. Oligomerized MLKL translocate to the plasma membrane and induces the membrane rupture and cell lysis.…”

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

“…In addition to necrosis and apoptosis, necroptosis is also observed in renal cells after CDDP treatment. Deletion of genes involved in necroptotic pathway (receptor-interacting protein 1 (RIP1) and mixed lineage kinase domain-like protein (MLKL)) managed to protect experimental animals against CDDP-induced AKI [61, 62] indicating that pharmacological inhibitors of these molecules could be considered as possible therapeutic agents for the attenuation of CDDP-caused nephrotoxicity.…”

Cell death–mediated cytokine release and its therapeutic implications

“…In kidneys, ischemia-reperfusion injury is promoted by RIPK3 and MLKL, apparently by regulating the cell death of renal proximal tubular cells, with subsequent recruitment of macrophages and NLRP3 inflammasome activation. Inhibitors targeting RIPK1, RIPK3, and MLKL appear to reduce this kidney damage, but MLKL deficiency alone does not necessarily protect from kidney reperfusion injury, suggesting there may be other interacting forms of cell death that drive injury (Linkermann et al, 2013; Newton et al, 2016; Anders, 2018; Chen et al, 2018a). In the liver, alcohol-induced damage was reduced in the absence of RIPK3 and MLKL, suggesting that necroptosis promotes disease (Roychowdhury et al, 2013; Wang et al, 2016).…”