Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity

Tristão, Vivian Regina; Pessoa, Edson Andrade; Nakamichi, Renata; Reis, Luciana Aparecida; Batista, Marcelo Costa; Durão, Marcelino de Souza; Monte, Julio Cesar Martins

doi:10.1007/s10495-015-1190-5

Cited by 40 publications

(35 citation statements)

References 35 publications

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“…Signs of an ongoing necroptotic response (e.g., increased RIPK1, RIPK3, and/or MLKL expression and/or phosphorylation levels) are common to various renal disorders (at least in mice), including acute kidney injury (AKI) caused by I/R (115, 119, 162), urolithiasis (163), cisplatin-based chemotherapy or radiocontrast (115, 164–167), and chronic kidney disease after unilateral nephrectomy (168). Nec-1 mediates nephroprotective effects in virtually all these settings, which supports the contention that necroptosis contributes to the etiology of various renal disorders, at least in mice.…”

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

“…Similar data were obtained with Nec-1, SfA, and 16–86, employed alone or in combination (115, 165), which suggests that various forms of necrotic RCD contribute to the etiology of AKI. Some authors report that Z-VAD-fmk can enhance the nephroprotective effects of Nec-1 in models of cisplatin-induced AKI (164, 167), whereas others demonstrate that Z-VAD-fmk has no beneficial effects in mice experiencing radiocontrast- or I/R-driven AKI (162, 165). This apparent discrepancy may stem from the capacity of cisplatin to trigger apoptotic RCD in some tubule cells and necroptosis in others.…”

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

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Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

512

398

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Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.

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Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

512

398

View full text Add to dashboard Cite

show abstract

“…Injecting radiocontrast medium 24 h after IR induced further contrast-induced AKI, a type of injury also reversible with Nec-1 [6]. Two independent groups consistently reported that Nec-1 attenuates tubular cell injury in cisplatin-induced AKI in mice [7, 8]. Another group reported Nec-1 to attenuate rhabdomyolysis-induced AKI triggered by intramuscular injection of glycerol [9].…”

Section: Essential Proteins Of the Necroptosis Pathway Contributing Tmentioning

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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“…High RIPK3 expression may facilitate the aggregation of RIPK3 oligomers to a higher-order structure (referred to as the necrosome) that induces MLKL phosphorylation. [9][10][11][12] Ferroptosis is an iron-dependent regulated necrosis subroutine characterized by increased lipid peroxidation resulting from lack of activity of the glutathione peroxidase 4 that requires glutathione to function. Necroptosis is an important contributor to tissue injury in the heart, skin, and intestine, but its contribution to renal injury is incompletely characterized.…”

mentioning

confidence: 99%

Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI

Martín‐Sánchez¹,

Ruiz‐Andrés²,

Poveda³

et al. 2016

JASN

408

382

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AKI is histologically characterized by necrotic cell death and inflammation. Diverse pathways of regulated necrosis have been reported to contribute to AKI, but the molecular regulators involved remain unclear. We explored the relative contributions of ferroptosis and necroptosis to folic acid (FA)-induced AKI in mice. FA-AKI in mice associates with lipid peroxidation and downregulation of glutathione metabolism proteins, features that are typical of ferroptotic cell death. We show that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, preserved renal function and decreased histologic injury, oxidative stress, and tubular cell death in this model. With respect to the immunogenicity of ferroptosis, Fer-1 prevented the upregulation of IL-33, an alarmin linked to necroptosis, and other chemokines and cytokines and prevented macrophage infiltration and Klotho downregulation. In contrast, the pancaspase inhibitor zVAD-fmk did not protect against FA-AKI. Additionally, although FA-AKI resulted in increased protein expression of the necroptosis mediators receptor-interacting protein kinase 3 (RIPK3) and mixed lineage domain-like protein (MLKL), targeting necroptosis with the RIPK1 inhibitor necrostatin-1 or genetic deficiency of RIPK3 or MLKL did not preserve renal function. Indeed, compared with wild-type mice, MLKL knockout mice displayed more severe AKI. However, RIPK3 knockout mice with AKI had less inflammation than their wild-type counterparts, and this effect associated with higher IL-10 concentration and regulatory T cell-to-leukocyte ratio in RIPK3 knockout mice. These data suggest that ferroptosis is the primary cause of FA-AKI and that immunogenicity secondary to ferroptosis may further worsen the damage, although necroptosis-related proteins may have additional roles in AKI.

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Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity

Cited by 40 publications

References 35 publications

Necroptosis: Mechanisms and Relevance to Disease

Necroptosis: Mechanisms and Relevance to Disease

Necroptosis in Acute Kidney Injury

Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI

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