Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury.
Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury.
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DOI：
10.1016/j.kint.2017.01.014
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发表时间：
2017-07
影响因子：
19.6
通讯作者：
Shinji Tanaka;Tetsuhiro Tanaka;Takahisa Kawakami;H. Takano;M. Sugahara;H. Saito;Yoshiki Higashijima;Junna Yamaguchi;R. Inagi;M. Nangaku
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文献类型：
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作者：
Shinji Tanaka;Tetsuhiro Tanaka;Takahisa Kawakami;H. Takano;M. Sugahara;H. Saito;Yoshiki Higashijima;Junna Yamaguchi;R. Inagi;M. Nangaku
血管粘附蛋白-1 （VAP-1）是一种独特的分子，它既是粘附分子，又是催化伯胺氧化脱氨的外酶，并在细胞外空间产生过氧化氢。虽然VAP-1与多种炎症性疾病有关，但其在急性肾损伤中的作用尚不清楚。本研究在肾缺血再灌注损伤大鼠模型中研究VAP-1在肾脏中的表达及其抑制作用。VAP-1主要在周细胞中表达，周细胞释放酶活性酶。在体内，一种特异性的VAP-1抑制剂RTU-1096可以显著改善大鼠肾缺血/再灌注损伤，并在损伤后12小时降低中性粒细胞浸润，而不改变巨噬细胞或T淋巴细胞群。在中性粒细胞缺失大鼠中，VAP-1抑制的保护作用消失，提示其抑制通过抑制中性粒细胞浸润来改善肾缺血再灌注损伤。为了研究由VAP-1酶反应产生的过氧化氢是否会促进中性粒细胞的浸润，我们用纯化的人中性粒细胞进行了琼脂糖下迁移实验。重组人VAP-1显著诱导中性粒细胞迁移，RTU-1096或过氧化氢酶几乎完全抑制了中性粒细胞迁移。因此，VAP-1通过增强中性粒细胞浸润，产生局部过氧化氢梯度，在肾缺血/再灌注损伤的病理生理中起关键作用。因此，抑制VAP-1可能是一种治疗缺血性急性肾损伤的新方法。
Vascular adhesion protein-1 (VAP-1) is a unique molecule since it acts as an adhesion molecule as well as an ectoenzyme catalyzing oxidative deamination of primary amines and generates hydrogen peroxide in the extracellular space. While VAP-1 is implicated in various inflammatory diseases, its role in acute kidney injury is less characterized. Here we studied VAP-1 expression in the kidney and the effect of its inhibition in a rat model of renal ischemia/reperfusion injury. VAP-1 was predominantly expressed in pericytes, which released enzymatically active enzyme.In vivo, a specific VAP-1 inhibitor, RTU-1096, significantly ameliorated rat renal ischemia/reperfusion injury and decreased neutrophil infiltration measured 12 hours after injury without altering macrophage or T lymphocyte populations. The protective effect of VAP-1 inhibition was lost in neutrophil-depleted rats, suggesting its inhibition ameliorated renal ischemia/reperfusion injury by suppressing neutrophil infiltration. To investigate whether hydrogen peroxide generated by VAP-1 enzyme reaction enhances neutrophil infiltration, we conducted an under-agarose migration assay with purified human neutrophils. Recombinant human VAP-1 significantly induced neutrophil migration, which was almost completely inhibited by RTU-1096 or catalase. Thus, VAP-1 plays a critical role in the pathophysiology of renal ischemia/reperfusion injury by enhancement of neutrophil infiltration generating a local hydrogen peroxide gradient. Hence, VAP-1 inhibition may be a novel therapy in ischemic acute kidney injury.