Effect of a Novel Nuclear Factor-κB Activation Inhibitor on Renal Ischemia-Reperfusion Injury

Kono, Hidaka; Nakagawa, Ken; Morita, Shinya; Shinoda, Kazunobu; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Umezawa, Kazuo; Oya, Mototsugu

doi:10.1097/tp.0b013e3182a3df74

Cited by 17 publications

(18 citation statements)

References 30 publications

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“…[82–88]. In addition, ROS has been reported to participate in NF-κB pathway activation, which is unsurprising given the oxidant-sensitive properties of NF-κB [86].…”

Section: Discussionmentioning

confidence: 99%

Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation

et al. 2015

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BackgroundEarly acute kidney injury (AKI) in severely burned patients predicts a high mortality that is multi-factorial. Hydrogen has been reported to alleviate organ injury via selective quenching of reactive oxygen species. This study investigated the potential protective effects of hydrogen against severe burn-induced early AKI in rats.MethodsSevere burn were induced via immersing the shaved back of rats into a 100°C bath for 15 s. Fifty-six Sprague–Dawley rats were randomly divided into Sham, Burn + saline, and Burn + hydrogen-rich saline (HS) groups, and renal function and the apoptotic index were measured. Kidney histopathology and immunofluorescence staining, quantitative real-time PCR, ELISA and western blotting were performed on the sera or renal tissues of burned rats to explore the underlying effects and mechanisms at varying time points post burn.ResultsRenal function and tubular apoptosis were improved by HS treatment. In addition, the oxidation–reduction potential and malondialdehyde levels were markedly reduced with HS treatment, whereas endogenous antioxidant enzyme activities were significantly increased. HS also decreased the myeloperoxidase levels and influenced the release of inflammatory mediators in the sera and renal tissues of the burned rats. The regulatory effects of HS included the inhibition of p38, JNK, ERK and NF-κB activation, and an increase in Akt phosphorylation.ConclusionHydrogen can attenuate severe burn-induced early AKI; the mechanisms of protection include the inhibition of oxidative stress induced apoptosis and inflammation, which may be mediated by regulation of the MAPKs, Akt and NF-κB signalling pathways.

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“…[82–88]. In addition, ROS has been reported to participate in NF-κB pathway activation, which is unsurprising given the oxidant-sensitive properties of NF-κB [86].…”

Section: Discussionmentioning

confidence: 99%

Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation

et al. 2015

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“…Inflammation is invariably found to be an important initiating and aggravating factor in both acute and chronic kidney injury ( 13 ). Nuclear factor-κB (NF-κB), a pivotal mediator of the inflammatory response, modulates the expression levels of adhesion molecules, chemokines and other pro-inflammatory molecules in the kidney ( 14 , 15 ). It was reported that interleukin (IL)-4 promoted the activation of signal transducer and activator of transcription 6 (STAT6), suppressing the transcriptional activation of NF-κB-dependent proinflammatory mediators following liver IRI ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF-κB pathway in ischemia/reperfusion injury after renal transplantation

Zhang

Zhao

et al. 2017

Int J Mol Med

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Ischemia/reperfusion injury (IRI) commonly occurs in renal transplantation. Erythropoietin (EPO) exerts a protective effect in IRI. To investigate the underlying molecular mechanism, rat models of renal IRI were established and treated with EPO and/or lentivirus-mediated EPO-siRNA, the signal transducer and activator of transcription 6 (STAT6) inhibitor AS1517499, the JNK inhibitor SP600125, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, and the nuclear factor (NF)-κB inhibitor lactacystin. Histological examination revealed that EPO protected the kidney from IRI, through decreasing the extent of tissue congestion and inflammatory cell infiltration; however, EPO siRNA did not exert the same protective effect. In addition, the EPO level was inversely associated with renal IRI. EPO downregulated the expression of interferon-γ, interleukin (IL)-4, creatinine and caspase-3, and upregulated the expression of IL-10, thymic stromal lymphopoietin, STAT6, p-JNK and p-p38, while the opposite effects were observed with the administration of EPO-siRNA and the specific respective inhibitors. Further results revealed that MAPK (p-JNK and p-p38) acted upstream of NF-κB, and that NF-κB signaling regulated the expression of caspase-1 and -3, which may be responsible for the cytotoxicity associated with IRI. Taken together, the results of the present study demonstrated that EPO exerted a protective effect in renal IRI via the STAT6/MAPK/NF-κB pathway. This protective effect of EPO may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients.

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“…Inflammation is an invariable finding in acute and chronic kidney injury ( 12 ) and is a critical initiating and aggravating factor in kidney damage ( 13 ). A pivotal mediator of this inflammatory response is the transcription factor nuclear factor-κB (NF-κB), which regulates the expression of adhesion molecules, chemokines and other pro-inflammatory molecules in renal or endothelial cells (ECs) ( 14 – 16 ). The best-characterized signaling pathways that lead to NF-κB activation are those stimulated by members of the interleukin-1 (IL-1)/Toll-like receptor family and tumor necrosis factor-α (TNF-α) ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Hypothermic machine perfusion increases A20 expression which protects renal cells against ischemia/reperfusion injury by suppressing inflammation, apoptosis and necroptosis

Yang

Zhong

et al. 2016

International Journal of Molecular Medicine

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There is an urgent need to improve the quality of donor organs obtained after cardiac death. In the present study, we examined the potential mechanisms through which A20 protects renal cells against ischemia/reperfusion injury (IRI) following either hypothermic machine perfusion (HMP) or static cold storage (CS) of the kidneys in a rabbit model. The expression of markers of apoptosis, necroptosis and inflammation in frozen kidney tissues were detected by western blot analysis, RT-qPCR and ELISA. Compared with the CS group, A20 expression was significantly higher in the tissue from the HMP group (P<0.01). By contrast, the expression of nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) was significantly lower in HMP group (P<0.01), whereas IκBα expression was significantly higher (P<0.01). The expression of apoptosis signal-regulating kinase 1 (ASK1), phosphorylated (p-)c-Jun N-terminal kinase (JNK) and activated caspase-3 in the HMP group was significantly downregulated compared with that in the CS group (all P<0.01). In addition, A20 inhibited receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis in the kidney. RIPK3 expression in the HMP group was significantly lower than that in the CS group (P<0.01), although the levels in both groups were higher than those in the sham group (P<0.01). Based on these findings, we propose a novel mechanism underlying the anti-apoptotic effect of A20 in renal cells in which A20 binds to ASK1 and promotes the degradation of ASK1 leading to the suppression of JNK activation and eventually, to the blockade of apoptosis. Thus, HMP reduces inflammation, apoptosis and necroptosis by upregulating the expression of A20; this mechanism may be responsible for protecting the kidney against IRI.

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Effect of a Novel Nuclear Factor-κB Activation Inhibitor on Renal Ischemia-Reperfusion Injury

Abstract: Treatment with DHMEQ before renal artery clamping may therefore be useful for renal I/R injury and application to renal transplantation is expected.

Cited by 17 publications

References 30 publications

Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation

Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation

Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF-κB pathway in ischemia/reperfusion injury after renal transplantation

Hypothermic machine perfusion increases A20 expression which protects renal cells against ischemia/reperfusion injury by suppressing inflammation, apoptosis and necroptosis

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