Protease-activated receptor 2 exacerbates adenine-induced renal tubulointerstitial injury in mice
Protease-activated receptor 2 exacerbates adenine-induced renal tubulointerstitial injury in mice
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DOI：
10.1016/j.bbrc.2016.12.108
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发表时间：
2017-01-29
影响因子：
3.1
通讯作者：
Takahashi, Nobuyuki
中科院分区：
文献类型：
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作者：
Hayashi, Sakiko;Oe, Yuji;Takahashi, Nobuyuki
高凝性与慢性肾脏疾病（CKD）有关。已知凝血级联中的组织因子/因子VIIa复合物和因子Xa可激活蛋白酶活化受体2 (PAR2)，并引起炎症和组织损伤。尽管PAR2在肾脏中高表达，但尚不清楚PAR2是否在CKD中起致病作用。为了验证这一点，我们给缺乏Par2 （F2rl1(-/-)）和野生型（F2rl1(-/-)）的小鼠喂食腺嘌呤饮食，以诱导小管间质损伤，这是CKD的标志。腺嘌呤处理小鼠表现出严重的肾功能障碍、肾小管萎缩和纤维化。大鼠肾脏纤维蛋白沉积、组织因子和PARs表达明显增高。缺乏Par2可减轻肾组织损伤，降低炎症、纤维化和氧化应激相关基因的表达水平。我们的数据表明，PAR2在腺嘌呤诱导的小管损伤的发病机制中至关重要。正在开发的PAR2拮抗剂可用于治疗和预防CKD。(C) 2016 Elsevier Inc.版权所有。
Hypercoagulability is associated with chronic kidney disease (CKD). Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade are known to activate proteaseeactivated receptor 2 (PAR2), and to cause inflammation and tissue injury. Although PAR2 is highly expressed in the kidney, it is unclear whether PAR2 plays a pathogenic role in CKD. To test this, we fed the mice lacking Par2 (F2rl1(-/-)) and wild type (F2rl1(-/-)) mice with adenine diet to induce tubulointerstitial injury, a hallmark of CKD. Adenine-treated mice showed severe renal dysfunction, tubular atrophy, and fibrosis. Fibrin deposition and the expression of tissue factor and PARs markedly increased in their kidneys. Lack of Par2 attenuated renal histological damage and reduced the expression levels of genes related to inflammation, fibrosis, and oxidative stress. Our data indicate that PAR2 is critically important in the pathogenesis of adenineinduced tubular injury. PAR2 antagonists under development could be useful to treat and prevent CKD. (C) 2016 Elsevier Inc. All rights reserved.