Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
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DOI：
10.1097/txd.0000000000000881
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发表时间：
2019-04-01
影响因子：
2.3
通讯作者：
Cowan, Peter J.
中科院分区：
文献类型：
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作者：
Bongoni, Anjan K.;Lu, Bo;Cowan, Peter J.
背景：补体激活在肾缺血再灌注损伤(IRI)的发病机制中起重要作用，但这是否涉及血管保护的内皮糖基化反应尚不清楚。我们在小鼠肾IRI模型中研究了补体激活对糖萼完整性和肾功能障碍的影响。方法雄性C57BL/6小鼠右肾切除，造成左肾缺血22min，再灌注24小时后处死，分析肾功能、补体激活、糖萼损伤、内皮细胞激活、炎症反应及中性粒细胞和巨噬细胞的浸润情况。结果大鼠肾缺血再灌注损伤严重，主要表现为血肌酐和尿素显著升高，补体活化和沉积明显增加，糖基化功能丧失，内皮细胞活化，炎症反应和天然细胞浸润。经抗C5抗体BB5.1治疗后，血清肌酐(P=0.04)和尿素(P=0.003)、组织C3b/c和C9沉积(P=0.004)、血浆C3b(P=0.001)和C5a(P=0.006)、血管内皮细胞黏附分子-1表达(P=0.003)、糖萼脱落(组织硫酸乙酰肝素[P=0.001]、血浆Syndecan-1[P=0.007]和透明质酸[P=0.02])均显著降低。炎症(高迁移率组Box-1[P=0.0003])，组织中性粒细胞(P=0.0009)和巨噬细胞(P=0.004)浸润。结论补体激活的终末通路在肾缺血再灌注损伤中起关键作用，其损伤机制与肾小管上皮细胞的脱落有关。
Background Complement activation plays an important role in the pathogenesis of renal ischemia-reperfusion (IR) injury (IRI), but whether this involves damage to the vasculoprotective endothelial glycocalyx is not clear. We investigated the impact of complement activation on glycocalyx integrity and renal dysfunction in a mouse model of renal IRI. Methods Right nephrectomized male C57BL/6 mice were subjected to 22 minutes left renal ischemia and sacrificed 24 hours after reperfusion to analyze renal function, complement activation, glycocalyx damage, endothelial cell activation, inflammation, and infiltration of neutrophils and macrophages. Results Ischemia-reperfusion induced severe renal injury, manifested by significantly increased serum creatinine and urea, complement activation and deposition, loss of glycocalyx, endothelial activation, inflammation, and innate cell infiltration. Treatment with the anti-C5 antibody BB5.1 protected against IRI as indicated by significantly lower serum creatinine (P = 0.04) and urea (P = 0.003), tissue C3b/c and C9 deposition (both P = 0.004), plasma C3b (P = 0.001) and C5a (P = 0.006), endothelial vascular cell adhesion molecule-1 expression (P = 0.003), glycocalyx shedding (tissue heparan sulfate [P = 0.001], plasma syndecan-1 [P = 0.007], and hyaluronan [P = 0.02]), inflammation (high mobility group box-1 [P = 0.0003]), and tissue neutrophil (P = 0.0009) and macrophage (P = 0.004) infiltration. Conclusions Together, our data confirm that the terminal pathway of complement activation plays a key role in renal IRI and demonstrate that the mechanism of injury involves shedding of the glycocalyx.