Functional regulation of von Willebrand factor ameliorates acute ischemia-reperfusion kidney injury in mice

Shiro Ono,Mitsuhiko Sugimoto,Kiyomi Yoshimoto,Toshiyuki Miyata,Hideto Matsui,Kenji Nishio,Noritaka Yada,Masashi Noda,Masashi Akiyama,Shogo Kasuda

doi:10.1038/s41598-019-51013-2

Shiro Ono, Mitsuhiko Sugimoto + Show 8 more

Open Access

https://doi.org/10.1038/s41598-019-51013-2

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Abstract

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.

Highlights

Acute kidney injury (AKI), defined as sudden renal failure or damage that occurs within a few hours or days, is often seen in clinical settings and its mortality remains high even in developed countries[1,2]
Recent mouse model studies by our group and others demonstrated that von Willebrand factor (VWF) is critically involved in the pathophysiology of I/R injuries in various organs, such as the heart, brain and liver[12,13,14,15,17]
Our results revealed that following I/R kidney injury, VWF-KO mice exhibited less kidney damage than WT mice

Summary

Introduction

Acute kidney injury (AKI), defined as sudden renal failure or damage that occurs within a few hours or days, is often seen in clinical settings and its mortality remains high even in developed countries[1,2]. Ischemia-induced endothelial dysfunction or excessive inflammatory responses may be involved in the pathophysiology of I/R injury, leading to acute organ failure[3,4,5]. We hypothesized that VWF-dependent thrombotic or inflammatory responses may be involved in I/R kidney injury. In this regard, a very recent study by others[16] suggested that recombinant ADAMTS13 could be effective to improve renal ischemia-reperfusion injury. Consistent with the RBF data, the serum creatinine value in VWF-KO mice is significantly (*p < 0.05) lower than that in WT mice. The RBF and serum creatinine values demonstrated that kidney damages during reperfusion was less extensive in VWF-KO mice than in WT controls, and that the administration of rADAMTS13 significantly improved kidney damages in WT mice. Injury, we explored the functional relevance of the VWF-ADAMTS13 axis in this pathologic condition and the therapeutic potential of regulating VWF functions

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