Protective Effect of Neutralization of the Extracellular High-Mobility Group Box 1 on Renal Ischemia-Reperfusion Injury in Miniature Swine

Miura, Kiyonori; Sahara, H.; Sekijima, M.; Kawai, Maki; Waki, S.; Nishimura, Hiroaki; Setoyama, Kentaro; Clayman, Eric; Shimizu, Akira; Yamada, Kazuhiko

doi:10.1097/tp.0000000000000358

Cited by 21 publications

(17 citation statements)

References 31 publications

(18 reference statements)

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“…Anti-HMGB1 antibody is reported to have a neutralizing effect on renal ischemia-reperfusion injury, and it also suppresses the number of apoptotic cells [25]. The results of this study show not only a reduction of apoptotic cells, but also a downregulation of JNK and TNF-α expression in kidney.…”

Section: Discussionsupporting

confidence: 51%

“…Firstly, apoptosis has been reported to be involved in kidney damage at the cellular level after experimental CS [25, 30]. In fact, necrosis is also involved in kidney damage [25]. It is unilateral that we choose apoptosis to detect cellular survival status.…”

Section: Discussionmentioning

confidence: 99%

“…Dimethyl sulfoxide (DMSO) was used as a solubilizer. The dosage of anti-TNF-α antibody (5 μg/200 μl), SP600125 (10 μg/200 μl), and anti-HMGB1 antibody (2.5 μg/200 μl) [25] was based on previous studies. In the vehicle group, only the same amount of DMSO was injected.…”

Section: Methodsmentioning

confidence: 99%

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Anti-high mobility group box-1 (HMGB1) antibody attenuates kidney damage following experimental crush injury and the possible role of the tumor necrosis factor-α and c-Jun N-terminal kinase pathway

et al. 2017

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BackgroundInflammation plays a crucial role in kidney damage after crush syndrome (CS). Several researchers report that high mobility group box-1 protein (HMGB1) may be the vital trigger in kidney damage, and tumor necrosis factor-α (TNF-α) and c-Jun N-terminal kinase (JNK) are involve in this pathophysiological process, but their biological roles are unclear. This study aimed to explore the relationship between HMGB1, JNK, and TNF-α in kidney damage.MethodsThe crush injury model was established using weight compression. The reliability of the crush injury model was determined by hematoxylin-eosin (HE) staining. Western blot was used to detect the expression of HMGB1, JNK, and TNF-α, and TUNEL was used to mark apoptotic cells in the renal cortex.ResultsThe results showed that the highest expression of HMGB1 in muscle was 12 h after CS. JNK and TNF-α increased and peaked at 1 day after CS in kidneys. Western blot analysis revealed that anti-HMGB1 antibody could downregulate the expression of JNK and TNF-α. Anti-TNF-α could downregulate activation of JNK, and SP600125 could downregulate expression of TNF-α in the kidneys. In addition, anti-HMGB1 antibody, anti-TNF-α antibody, and SP600125 could reduce cellular apoptosis in the renal cortex.ConclusionsIt is possible that JNK and TNF-α commonly contribute to kidney damage by assembling a positive feedback cycle after CS, leading to increased apoptosis in the renal cortex. HMGB1 from the muscle may be the trigger.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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Anti-high mobility group box-1 (HMGB1) antibody attenuates kidney damage following experimental crush injury and the possible role of the tumor necrosis factor-α and c-Jun N-terminal kinase pathway

et al. 2017

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“…2, 3 One such insult is ischemia reperfusion injury (IRI). 4 IRI is an unavoidable complication in the process of cardiac transplantation, with the donor heart rendered ischemic for prolonged periods prior to implantation into the recipient and subsequent reperfusion. These processes damage the cardiac graft via activation of innate immune mechanisms, and the severity of this early inflammation and injury is associated with the ferocity and intensity of a subsequent adaptive immune response.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity

et al. 2015

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In this study, we developed a stable, nontoxic novel micelle nanoparticle to attenuate responses of endothelial cell (EC) inflammation when subjected to oxidative stress, such as observed in organ transplantation. Targeted Rapamycin Micelles (TRaM) were synthesized using PEG-PE-amine and N-palmitoyl homocysteine (PHC) with further tailoring of the micelle using targeting peptides (cRGD) and labeling with far-red fluorescent dye for tracking during cellular uptake studies. Our results revealed that the TRaM was approximately 10 nm in diameter and underwent successful internalization in Human Umbilical Vein EC (HUVEC) lines. Uptake efficiency of TRaM nanoparticles was improved with the addition of a targeting moiety. In addition, our TRaM therapy was able to downregulate both mouse cardiac endothelial cell (MCEC) and HUVEC production and release of the pro-inflammatory cytokines, IL-6 and IL-8 in normal oxygen tension and hypoxic conditions. We were also able to demonstrate a dose-dependent uptake of TRaM therapy into biologic tissues ex vivo. Taken together, these data demonstrate the feasibility of targeted drug delivery in transplantation, which has the potential for conferring local immunosuppressive effects without systemic consequences while also dampening endothelial cell injury responses.

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“…HMGB1 can be targeted in various ways, including inhibiting HMGB1 release, targeting HMGB1 directly, and blocking HMGB1 receptors. Both in vivo and in vitro studies found that in various pathological conditions, application of HMGB1 antagonists reduces inflammatory reactions [32][33][34]. It seems that interventions targeting the HMGB1-receptor axis provide more targets for treatment, which may be more amendable to the clinic.…”

Section: Intervention With Hmgb1 Antagonistsmentioning

confidence: 99%

Role of high-mobility group box 1 protein in inflammatory bowel disease

Wang

Gong

et al. 2015

Inflamm. Res.

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High-mobility group box 1 (HMGB1) protein is a nuclear non-histone DNA-binding protein. It is released into the extracellular milieu and mediates inflammatory responses, which contribute to the pathogenesis of numerous inflammatory diseases, including inflammatory bowel disease (IBD). An online search was performed in PubMed and Web of Science databases for articles providing evidence on the role of HMGB1 in IBD. HMGB1 plays an important role in IBD pathogenesis. Application of HMGB1 antagonists reduced inflammatory reactions and ameliorated colitis in rodent models, which may provide new insights into the diagnosis and treatment of IBD.

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Protective Effect of Neutralization of the Extracellular High-Mobility Group Box 1 on Renal Ischemia-Reperfusion Injury in Miniature Swine

Abstract: In this study, we demonstrated the beneficial effects of perioperative administration of anti-HMGB1 antibody in reducing renal IRI in a clinically relevant, large animal model.

Cited by 21 publications

References 31 publications

Anti-high mobility group box-1 (HMGB1) antibody attenuates kidney damage following experimental crush injury and the possible role of the tumor necrosis factor-α and c-Jun N-terminal kinase pathway

Anti-high mobility group box-1 (HMGB1) antibody attenuates kidney damage following experimental crush injury and the possible role of the tumor necrosis factor-α and c-Jun N-terminal kinase pathway

Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity

Role of high-mobility group box 1 protein in inflammatory bowel disease

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