Glycyrrhizic Acid Ameliorates HMGB1-Mediated Cell Death and Inflammation after Renal Ischemia Reperfusion Injury
Glycyrrhizic Acid Ameliorates HMGB1-Mediated Cell Death and Inflammation after Renal Ischemia Reperfusion Injury
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DOI：
10.1159/000364908
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
Jevnikar, Anthony M.
中科院分区：
文献类型：
--
作者：
Lau, Arthur;Wang, Shuang;Jevnikar, Anthony M.
背景资料：肾缺血再灌注损伤（IRI）可导致急性肾损伤（阿基）和肾小管上皮细胞（TEC）死亡，死亡细胞释放的高密度脂蛋白族蛋白B1（HMGB 1）等损伤相关分子模式可通过影响TEC而促进器官功能障碍和炎症反应。甘草酸（GZA）是HMGB 1的功能性抑制剂，但其减弱HMGB 1介导的TEC损伤的能力尚未被测试。方法/结果：在体外，缺氧和细胞因子处理杀死TEC，导致HMGB 1逐渐释放到上清液中。GZA减少缺氧诱导的TEC死亡，如通过膜联蛋白-V和碘化丙啶测量的。低氧可增加TEC中MCP-1和CXCL 1的表达，GZA可剂量依赖性地降低其表达。同样，GZA抑制效应NK细胞的HMGB 1活化。为了测试GZA在体内中和HMGB 1的效果，对小鼠进行肾IRI。HMGB 1蛋白表达在缺血后4 ~ 24 h呈进行性增加，4 h时在肾小管上皮细胞中可见表达。通过组织学分析和乙锭同源二聚体染色，GZA在IRI后保留了肾功能，并减少了肾小管坏死和中性粒细胞浸润。结论：重要的是，这些数据首次证明缺氧后的阿基和肾IRI可能通过HMGB 1释放而促进，这可以减少TEC的存活并增加炎症。通过GZA抑制HMGB 1与TEC的相互作用可能是减轻IRI和移植后肾损伤的治疗策略。(c)2014 S. Karger AG，巴塞尔
Background: Renal ischemia reperfusion injury (IRI) leads to acute kidney injury (AKI) and the death of tubular epithelial cells (TEC).The release of high-nnobility group box-1 (HMGB1) and other damage-associated molecular pattern moieties from dying cells may promote organ dysfunction and inflammation by effects on TEC. Glycyrrhizic acid (GZA) is a functional inhibitor of HMGB1, but its ability to attenuate the HMGB1-mediated injury of TEC has not been tested. Methods/Results: In vitro, hypoxia and cytokine treatment killed TEC and resulted in the progressive release of HMGB1 into the supernatant. GZA reduced the hypoxia-induced TEC death as measured by annexin-V and propidium iodide. Hypoxia increased the expression of MCP-1 and CXCL1 in TEC, which was reduced by GZA in a dose-dependent manner. Similarly, the HMGB1 activation of effector NK cells was inhibited by GZA. To test the effect of HMGB1 neutralization by GZA in vivo, mice were subjected to renal IRI. HMGB1 protein expression increased progressively in kidneys from 4 to 24 h after ischemia and was detected in tubular cells by 4 h using imnnunohistochemistry. GZA preserved renal function after IRI and reduced tubular necrosis and neutrophil infiltration by histological analyses and ethidium homodimer staining. Conclusions: Importantly, these data demonstrate for the first time that AKI following hypoxia and renal IRI may be promoted by HMGB1 release, which can reduce the survival of TEC and augment inflammation. Inhibition of the interaction of HMGB1 with TEC through GZA may represent a therapeutic strategy for the attenuation of renal injury following IRI and transplantation. (c) 2014 S. Karger AG, Basel