Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity
Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity
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DOI：
10.3390/ijms20174140
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发表时间：
2019-08
影响因子：
5.6
通讯作者：
Yuki Narita;Kana Hamamura;Mami Kashiyama;Sara Utsumi;Y. Kakizoe;Yuki Kondo;Yoichi Ishitsuka;H. Jono;T. Irie;M. Mukoyama;H. Saito;D. Kadowaki;S. Hirata;K. Kitamura
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文献类型：
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作者：
Yuki Narita;Kana Hamamura;Mami Kashiyama;Sara Utsumi;Y. Kakizoe;Yuki Kondo;Yoichi Ishitsuka;H. Jono;T. Irie;M. Mukoyama;H. Saito;D. Kadowaki;S. Hirata;K. Kitamura
氧化应激、炎症和组织纤维化之间的相互作用导致慢性肾脏病（CKD）的进展。依度沙班是一种活化凝血因子Xa（FXa）抑制剂，通过抑制动物模型中的炎症和组织纤维化来改善肾脏疾病。有趣的是，另一种FXa抑制剂利伐沙班抑制FXa诱导的氧化应激。因此，FXa抑制剂可能是针对CKD进展的上述三个风险因素的多靶点药物。然而，负责引起FXa抑制剂的抗氧化作用的确切机制仍不清楚。在这项研究中，依度沙班的抗氧化作用进行了评价。首先，使用人近端肾小管细胞（HK-2细胞）评价依度沙班的细胞内抗氧化特性。接着，使用电子自旋共振和荧光分析方法测量直接自由基清除活性。结果表明，依多沙班对FXa、硫酸吲哚酚和血管紧张素II诱导的HK-2细胞氧化应激具有抗氧化作用，FXa抑制活性参与了部分抗氧化机制。此外，依度沙班通过其结构特异性的直接自由基清除活性发挥其抗氧化作用。艾度沙班通过抑制FXa和直接清除自由基活性发挥抗氧化作用，因此，可作为与CKD进展相关的三个主要风险因素的多靶点药物。
The interplay between oxidative stress, inflammation, and tissue fibrosis leads to the progression of chronic kidney disease (CKD). Edoxaban, an activated blood coagulation factor Xa (FXa) inhibitor, ameliorates kidney disease by suppressing inflammation and tissue fibrosis in animal models. Interestingly, rivaroxaban, another FXa inhibitor, suppresses oxidative stress induced by FXa. Thus, FXa inhibitors could be multitargeted drugs for the three aforementioned risk factors for the progression of CKD. However, the exact mechanism responsible for eliciting the antioxidant effect of FXa inhibitors remains unclear. In this study, the antioxidant effect of edoxaban was evaluated. First, the intracellular antioxidant properties of edoxaban were evaluated using human proximal tubular cells (HK-2 cells). Next, direct radical scavenging activity was measured using the electron spin resonance and fluorescence analysis methods. Results show that edoxaban exhibited antioxidant effects on oxidative stress induced by FXa, indoxyl sulfate, and angiotensin II in HK-2 cells, as well as the FXa inhibitory activity, was involved in part of the antioxidant mechanism. Moreover, edoxaban exerted its antioxidative effect through its structure-specific direct radical scavenging activity. Edoxaban exerts antioxidant effects by inhibiting FXa and through direct radical-scavenging activity, and thus, may serve as multitargeted drugs for the three primary risk factors associated with progression of CKD.