Functional regulation of von Willebrand factor ameliorates acute ischemia-reperfusion kidney injury in mice
Functional regulation of von Willebrand factor ameliorates acute ischemia-reperfusion kidney injury in mice
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DOI：
10.1038/s41598-019-51013-2
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发表时间：
2019-10-08
影响因子：
4.6
通讯作者：
Nishio, Kenji
中科院分区：
文献类型：
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作者：
Ono, Shiro;Matsui, Hideto;Nishio, Kenji
急性肾损伤（阿基）是一种肾功能突然丧失，在临床环境中常见，并可能致命。除了止血功能外，已知血管性血友病因子（VWF）在炎症和血栓形成之间的相互作用中发挥作用。我们假设VWF可能参与阿基的病理生理学，其主要原因包括肾循环不足或肾脏中的炎性细胞浸润。为了验证这一假设，我们使用急性缺血再灌注（I/R）肾损伤的小鼠模型研究了VWF在阿基中的作用。我们分析了VWF基因缺失（敲除; KO）小鼠的肾功能和血流。在这种病理条件下，还评价了ADAMTS 13或功能阻断性抗VWF抗体对VWF的功能调节。与野生型（WT）小鼠相比，VWF-KO小鼠再灌注后观察到更大的肾血流量和更低的血清肌酐。组织学分析还显示VWF-KO小鼠肾组织中肾小管损伤和中性粒细胞浸润的程度显著较低。人重组ADAMTS 13和功能阻断性抗VWF抗体均显著改善WT小鼠的肾血流量、肾功能和组织学结果。我们的研究结果表明，VWF在阿基的发病机制中发挥作用。VWF的适当功能调节可以改善肾脏的微循环和血管功能，这表明了针对阿基的新的治疗选择。
Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and may become fatal. In addition to its hemostatic functions, von Willebrand factor (VWF) is known to play a role in cross-talk between inflammation and thrombosis. We hypothesized that VWF may be involved in the pathophysiology of AKI, major causes of which include insufficient renal circulation or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the role of VWF in AKI using a mouse model of acute ischemia-reperfusion (I/R) kidney injury. We analyzed renal function and blood flow in VWF-gene deleted (knock-out; KO) mice. The functional regulation of VWF by ADAMTS13 or a function-blocking anti-VWF antibody was also evaluated in this pathological condition. Greater renal blood flow and lower serum creatinine were observed after reperfusion in VWF-KO mice compared with wild-type (WT) mice. Histological analysis also revealed a significantly lower degree of tubular damage and neutrophil infiltration in kidney tissues of VWF-KO mice. Both human recombinant ADAMTS13 and a function-blocking anti-VWF antibody significantly improved renal blood flow, renal function and histological findings in WT mice. Our results indicate that VWF plays a role in the pathogenesis of AKI. Proper functional regulation of VWF may improve the microcirculation and vessel function in the kidney, suggesting a novel therapeutic option against AKI.