Factor Xa inhibitor, edoxaban ameliorates renal injury after subtotal nephrectomy by reducing epithelial-mesenchymal transition and inflammatory response.
Factor Xa inhibitor, edoxaban ameliorates renal injury after subtotal nephrectomy by reducing epithelial-mesenchymal transition and inflammatory response.
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DOI：
10.14814/phy2.15218
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发表时间：
2022-03
影响因子：
2.5
通讯作者：
Ouchi N
中科院分区：
文献类型：
--
作者：
Fang L;Ohashi K;Ogawa H;Otaka N;Kawanishi H;Takikawa T;Ozaki Y;Takahara K;Tatsumi M;Takefuji M;Murohara T;Ouchi N
慢性肾脏疾病（CKD）是世界范围内日益严重的威胁生命的疾病。最近的证据表明，凝血因子促进CKD患者肾功能障碍。激活因子X （FXa）抑制剂是预防房颤患者血栓形成的安全一线药物。本研究采用小鼠5/6肾切除模型研究依多沙班对CKD的治疗作用。8周龄野生型小鼠接受5/6次肾切除手术，随机分为两组，依多沙班组或混合饲料组。与对照组相比，edo沙班治疗导致尿白蛋白排泄量和血浆UN水平降低，并伴有肾小球横截面积和细胞数量减少。依多沙班治疗也能降低肾大部切除术后残余肾脏的纤维蛋白原阳性区域。此外，依多沙班治疗导致5/6肾切除术后小管间质纤维化减轻，并伴有残余肾脏上皮-间充质转化（EMT）标志物、炎症介质和氧化应激标志物的表达水平降低。用FXa蛋白处理培养的近端小管细胞HK‐2细胞，导致EMT标记物、炎症介质和氧化应激标记物的表达水平升高，而用依多沙班预处理可以消除这些标记物。用依多沙班处理HK‐2细胞可减弱FXa刺激的细胞外信号调节激酶（ERK）和NF‐κB的磷酸化水平。我们的研究结果表明，依多沙班可以通过降低EMT和炎症反应来改善肾大部切除术后的肾损伤，这表明FXa抑制可能是CKD合并心房颤动患者的一个新的治疗靶点。依多沙班治疗可改善肾大部切除术后的肾功能，并伴有EMT标记物、炎症介质和氧化应激标记物的增加。与此一致的是，用FXa处理HK‐2细胞会增加EMT标记物、炎症介质和氧化应激标记物，而依多沙班治疗会消除这些标记物。最后，FXa处理增加了ERK和NF - κB的磷酸化水平，而edoxaban通过PAR2依赖机制消除了这些磷酸化水平。因此，依多沙班可以通过减少EMT和炎症反应来改善肾损伤。
Chronic kidney disease (CKD) is an increasing and life‐threatening disease worldwide. Recent evidence indicates that blood coagulation factors promote renal dysfunction in CKD patients. Activated factor X (FXa) inhibitors are safe and first‐line drugs for the prevention of thrombosis in patients with atrial fibrillation. Here, we investigated the therapeutic effects of edoxaban on CKD using the mouse 5/6 nephrectomy model. Eight‐week‐old wild‐type mice were subjected to 5/6 nephrectomy surgery and randomly assigned to two groups, edoxaban or vehicle admixture diet. Edoxaban treatment led to reduction of urinary albumin excretion and plasma UN levels compared with vehicle group, which was accompanied with reduced glomerular cross‐sectional area and cell number. Edoxaban treatment also attenuated fibrinogen positive area in the remnant kidneys after subtotal nephrectomy. Moreover, edoxaban treatment resulted in attenuated tubulointerstitial fibrosis after 5/6 nephrectomy, which was accompanied by reduced expression levels of epithelial‐mesenchymal transition (EMT) markers, inflammatory mediators, and oxidative stress markers in the remnant kidneys. Treatment of cultured proximal tubular cells, HK‐2 cells, with FXa protein led to increased expression levels of EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by pretreatment with edoxaban. Treatment of HK‐2 cells with edoxaban attenuated FXa‐stimulated phosphorylation levels of extracellular signal‐regulated kinase (ERK) and NF‐κB. Our findings indicate that edoxaban can improve renal injury after subtotal nephrectomy by reducing EMT and inflammatory response, suggesting that FXa inhibition could be a novel therapeutic target for CKD patients with atrial fibrillation. Edoxaban treatment ameliorated renal function after subtotal nephrectomy with accompanying increases in EMT markers, inflammatory mediators, and oxidative stress markers. Consistently, treatment of HK‐2 cells with FXa increased EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by edoxaban treatment. Finally, FXa treatment increased phosphorylation levels of ERK and NF‐κB, which were abolished by edoxaban treatment through PAR2‐dependent mechanisms. Thus, edoxaban can improve renal injury by reducing EMT and inflammatory response.