Involvement of high mobility group box 1 in the pathogenesis of severe hemolytic uremic syndrome in a murine model
Involvement of high mobility group box 1 in the pathogenesis of severe hemolytic uremic syndrome in a murine model
复制标题
DOI：
10.1152/ajprenal.00263.2019
复制
发表时间：
2019-12-01
影响因子：
4.2
通讯作者：
Hosoya, Mitsuaki
中科院分区：
文献类型：
--
作者：
Maeda, Ryo;Kawasaki, Yukihiko;Hosoya, Mitsuaki
典型的溶血性尿毒症是由大肠杆菌的志贺毒素（Stx2）和脂多糖（LPS）引起的，可导致急性肾损伤。先天免疫在这一发病机制中的作用尚不清楚。我们在小鼠模型中分析了高迁移率组盒1 （HMGB1）在疾病发病中的作用。C57BL/6小鼠腹腔注射生理盐水（A组）、抗hmgb1单克隆抗体（B组）、Stx2和LPS引起严重疾病（C组），或Stx2、LPS和抗hmgb1抗体（D组）。实验第5天，C组小鼠全部死亡，D组小鼠全部存活。C组小鼠出现明显的贫血和血小板减少症，血浆肌酐水平仅在72 h时显著升高。而在毒素给药72 h后，C组小鼠肾小球组织表现出与人相似的病理特征，d组小鼠出现系膜细胞增殖。参与HMGB1信号传导的晚期糖基化终产物受体和NF-kappa B的表达在C组显著升高，而在d组则没有。在严重疾病小鼠模型中给予抗HMGB1抗体可抑制血浆HMGB1并促进组织损伤的改善。发现HMGB1参与疾病病理；因此，控制HMGB1活性可能会抑制疾病进展。
Typical hemolytic uremic syndrome is caused by Shiga toxin (Stx2) and lipopolysaccharide (LPS) of Escherichia coli and leads to acute kidney injury. The role of innate immunity in this pathogenesis is unclear. We analyzed the role of high mobility group box 1 (HMGB1) at the onset of disease in a murine model. C57BL/6 mice were intraperitoneally administered saline (group A), anti-HMGB1 monoclonal antibody (group B), Stx2 and LPS to elicit severe disease (group C), or Stx2, LPS, and anti-HMGB1 antibody (group D). While all mice in group C died by day 5 of the experiment, all mice in group D survived. Anemia and thrombocytopenia were pronounced and plasma creatinine levels were significantly elevated in group C only at 72 h. While at 72 h after toxin administration the glomerulus tissue in group C showed pathology similar to that of humans, mesangial cell proliferation was seen in group D. Plasma HMGB1 levels in group C peaked 3 h after administration and were higher than those in other groups. Expression of the receptor of advanced glycation end products and NF-kappa B, involved in HMGB1 signaling, was significantly elevated in group C but not in group D. Administration of anti-HMGB1 antibody in a murine model of severe disease inhibited plasma HMGB1 and promoted amelioration of tissue damage. HMGB1 was found to be involved in the disease pathology; therefore, controlling HMGB1 activity might inhibit disease progression.