An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury

Kers, Jesper; Leemans, Jaklien C.; Linkermann, Andreas

doi:10.1016/j.semnephrol.2016.03.002

Cited by 70 publications

(59 citation statements)

References 134 publications

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“…Necroptosis is only one subroutine of regulated necrosis and numerous other data exist showing that also other forms of regulated necrosis are involved in AKI [26]. As a broader concept, all forms of regulated necrosis induce inflammation via the release of alarmins and damage-associated molecular patterns (DAMPs) that activate a wide range of different pattern recognition receptors translating these danger signals into the secretion of proinflammatory cytokines and chemokines [27].…”

Section: Necroptosis As One Component Of Necroinflammation In Akimentioning

confidence: 99%

Necroptosis in Acute Kidney Injury

Anders¹

2018

Nephron

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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.

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Section: Necroptosis As One Component Of Necroinflammation In Akimentioning

confidence: 99%

Necroptosis in Acute Kidney Injury

Anders¹

2018

Nephron

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“…However, the physiological function of necroptosis upon similar perturbations in homeostasis has not been as well defined. Recently, multiple studies have suggested there are roles for necroptosis in development (2–5) and disease (reviewed in (6–8)), such as viral infection (9), atherosclerosis (10, 11), renal ischaemic reperfusion injury (12), and cancer (13–15). …”

Section: Introductionmentioning

confidence: 99%

“…1 However, the physiological function of necroptosis upon similar perturbations in homeostasis has not been as well defined. Recently, multiple studies have suggested there are roles for necroptosis in development [2][3][4][5] and disease [reviewed in (6)(7)(8)], such as viral infection, 9 atherosclerosis, 10,11 renal ischemic reperfusion injury, 12 and cancer. [13][14][15] The extrinsic pathway of apoptosis is initiated by ligation of death receptors, a subset of the tumor necrosis factor superfamily (TNFRSF) that includes tumor necrosis factor (TNF) receptor-1 (TNFR1; It has become evident that there is a bridge between apoptosis and necroptosis in homeostasis and disease.…”

Section: Introductionmentioning

confidence: 99%

Caspase‐8: regulating life and death

Tummers

Green

2017

Immunological Reviews

579

421

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Summary Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Whereas excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediatedactivation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

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“…The autonomous model provided two novel insights. First, cell death is a dynamical effect: death occurs when D * > S * , which is in stark contrast to the prevailing biomedical thought that sees cell death in terms of qualitative molecular pathways such as apoptosis, necrosis, and so on [15,[48][49][50][51]. Second, the theory gave a dynamical mechanism for therapy whereby a cell fated to die could be made to survive.…”

Section: Solving the Model Equationsmentioning

confidence: 99%

Nonautonomous dynamics of acute cell injury

et al. 2019

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Clinically-relevant forms of acute cell injury, which include stroke and myocardial infarction, have been of long-lasting challenge in terms of successful intervention and treatments. Although laboratory studies have shown it is possible to decrease cell death after such injuries, human clinical trials based on laboratory therapies have generally failed. We suggested these failures are due, at least partially, to the lack of a quantitative theoretical framework for acute cell injury. Here we provide a systematic study on a nonlinear dynamical model of acute cell injury and characterize the global dynamics of a nonautonomous version of the theory. The nonautonomous model gives rise to four qualitative types of dynamical patterns that can be mapped to the behavior of cells after clinical acute injuries. In addition, the concept of a maximum total intrinsic stress response, S max * , emerges from the nonautonomous theory. A continuous transition across the four qualitative patterns has been observed, which sets a natural range for initial conditions. Under these initial conditions in the parameter space tested, the total induced stress response can be increased to 2.5-11 folds of S max * . This result indicates that cells possess a reserve stress response capacity which provides a theoretical explanation of how therapies can prevent cell death after lethal injuries. This nonautonomous theory of acute cell injury thus provides a quantitative framework for understanding cell death and recovery and developing effective therapeutics for acute injury.

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An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury

Cited by 70 publications

References 134 publications

Necroptosis in Acute Kidney Injury

Necroptosis in Acute Kidney Injury

Caspase‐8: regulating life and death

Nonautonomous dynamics of acute cell injury

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