A Role for Tubular Necroptosis in Cisplatin-Induced AKI

Xu, Yanfang; Ma, Huabin; Shao, Jing; Wu, Jianfeng; Zhou, Linying; Zhang, Zhi Rong; Wang, Yuze; Huang, Zhenguo; Ren, Junming; Liu, Suhuan; Chen, Xiangmei; Han, Jiahuai

doi:10.1681/asn.2014080741

Cited by 275 publications

(264 citation statements)

References 31 publications

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“…Cisplatin damages the kidney by activating apoptosis and necroptosis signaling cascades 13 but also, by activating the innate and adaptive immune systems. Although RAS activation has been implicated in both regulating cell death and provoking inflammatory responses, we and others have struggled to reconcile the proinflammatory effects of global RAS activation with our more recent findings that AT 1 receptor activation directly on immune cells limits their production of inflammatory cytokines.…”

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confidence: 99%

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

Zhang¹,

Rudemiller²,

Patel³

et al. 2016

JASN

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Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT 1 ) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-a is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-a is suppressed or enhanced by AT 1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT 1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-a levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT 1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-a production induced by cisplatin. Finally, disrupting TNF-a production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-a levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT 1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.

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confidence: 99%

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

Zhang¹,

Rudemiller²,

Patel³

et al. 2016

JASN

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“…Although necrosis used to be considered as an unregulated form of cell death, necroptosis, a type of regulated necrosis, has been identified in ATN, as well as in drug-induced liver injury and ischemic brain injury (10)(11)(12). Mechanistically, RIP-1 phosphorylates RIP-3 and forms a necrosome (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, the necrosome phosphorylates MLKL, resulting in necroptosis in various types of cells (7,21). Inhibition of RIP-1 by Nec-1 and knockout of RIP-3 or MLKL prevents ATN in response to various stimuli, such as cisplatin, sepsis and ischemia/reperfusion injury (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

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NADPH oxidase inhibitor, diphenyleneiodonium prevents necroptosis in HK-2 cells

Dong

Chen

et al. 2017

Biomedical Reports

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Abstract. The aim of the present study was to investigate the protective effect of the NADPH oxidase inhibitor, diphenyleneiodonium (DPI) against necroptosis in renal tubular epithelial cells. A necroptosis model of HK-2 cells was established using tumor necrosis factor-α, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone and antimycin A (collectively termed TZA), as in our previous research. The necroptosis inhibitor, necrostatin-1 (Nec-1) or the NADPH oxidase inhibitor, DPI were administered to the necroptosis model. Production of reactive oxygen species (ROS) was detected by dichlorodihydrofluorescein diacetate in the different groups, and the manner of cell death was identified by flow cytometry. Western blot analysis was used to determine the levels of phosphorylation of receptor-interacting protein kinase 3 (RIP-3) and mixed lineage kinase domain-like (MLKL), which are essential to necroptosis. The results revealed that TZA increased the percentages of propidium iodide-positive HK-2 cells from 1.22±0.69 to 8.98±0.73% (P<0.001), and augmented the phosphorylation of RIP-3 and MLKL. ROS levels were increased in the TZA group compared with the control group (27.74±1. IntroductionAcute kidney injury (AKI) is a common clinical syndrome that is characterized by the rapid loss of kidney function and abrupt kidney damage. It is associated with high morbidity and mortality worldwide (1). Acute tubular necrosis (ATN) is the most common and severe pathological manifestation of AKI. Although necrosis has long been considered to be unregulated, previous studies have revealed various types of regulated necrosis that are independent of caspase activities (2). Necroptosis is an important type of regulated necrosis and is involved in various pathological conditions (3-7). Receptor-interacting protein kinase (RIP)-1 receives signals from various death stimuli, and subsequently recruits RIP-3 via RIP homotypic interaction motif domain-mediated interactions and promotes RIP-3 phosphorylation (8,9). Phosphorylated RIP-3 mediates the phosphorylation of mixed-lineage kinase domain-like (MLKL), ultimately leading to rupture of the plasma membrane (7). Previous studies have identified necroptosis in ATN induced by various stimuli, including ischemia/reperfusion, contrast medium and cisplatin (10-12). RIP-1 inhibition by necrostatin-1 (Nec-1), or knockout of RIP-3 or MLKL all prevent ATN (10-12).Reactive oxygen species (ROS) promote necroptosis in cardiomyocytes, liver cells, Jurkat cells and lung adenoma cells (13)(14)(15)(16). However, the effect of ROS on the necroptosis of renal tubular epithelium remains unknown. The present study hypothesized that excessive ROS production may promote necroptosis in HK-2 human kidney cells. Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, has been demonstrated to reduce ROS production and exert a protective role in numerous cell types (17)(18)(19)

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“…After being freely filtered through the glomerulus, unbound cisplatin accumulates in renal cells, especially proximal tubular cells. The accumulation of cisplatin leads to nuclear DNA damage, mitochondrial dysfunction, and tubular cell injury, resulting in cell death and causing acute kidney injury (AKI) [2-4]. …”

Section: Introductionmentioning

confidence: 99%

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

Jiao

Cai²,

Yu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data showed that the tubular β-catenin level was lower in AKI patients experiencing partial recovery than in patients experiencing complete recovery. Conclusion: The activation of the wnt/β-catenin pathway by CM protects against cisplatin-induced kidney injury, resulting in reduced apoptosis and intracellular ROS levels.

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A Role for Tubular Necroptosis in Cisplatin-Induced AKI

Cited by 275 publications

References 31 publications

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

NADPH oxidase inhibitor, diphenyleneiodonium prevents necroptosis in HK-2 cells

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

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