A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy
A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy
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DOI：
10.1016/j.jphs.2017.09.002
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发表时间：
2017-10-01
影响因子：
3.5
通讯作者：
Nishiyama, Akira
中科院分区：
文献类型：
--
作者：
Guan, Yu;Nakano, Daisuke;Nishiyama, Akira
肾脏表达蛋白酶激活受体-1（PAR-1）。PAR-1被认为是一种凝血酶受体，但其在肾损伤中的作用尚不清楚。在这项研究中，我们研究了PAR-1在肾小球损伤中的作用以及抑制PAR-1对肾病发展的影响。将小鼠分成3组：对照组、多柔比星+载体（15 mg/kg多柔比星和盐水）组和多柔比星+ Q94（15 mg/kg多柔比星和5 mg/kg/d PAR-1拮抗剂Q94）组。在指示的情况下，静脉内施用多柔比星，并通过皮下渗透微型泵施用PAR-1拮抗剂或盐水媒介物。PAR-1的表达在阿霉素处理的小鼠肾小球中增加。Q94治疗显著抑制了这些肾病小鼠中蛋白尿的增加。病理学分析表明，Q94治疗显着减弱过碘酸-希夫和结蛋白染色，足细胞损伤的指标，并降低肾小球足细胞蛋白和nephrin的水平。此外，凝血酶增加足细胞内钙离子水平。这种增加被抑制Q94和Rox 4560，瞬时受体电位阳离子通道（TRPC）3/6拮抗剂。此外，Q94和Rox 4560均抑制阿霉素诱导的足细胞中caspase-9和caspase-3活性的增加。这些数据表明，PAR-1有助于足细胞和肾小球损伤的发展，PAR-1拮抗剂具有治疗潜力。(C)2017作者Elsevier B. V.代表日本药理学会制作和主办。
The kidney expresses protease-activated receptor-1 (PAR-1). PAR-1 is known as a thrombin receptor, but its role in kidney injury is not well understood. In this study, we examined the contribution of PAR-1 to kidney glomerular injury and the effects of its inhibition on development of nephropathy. Mice were divided into 3 groups: control, doxorubicin + vehicle (15 mg/kg doxorubicin and saline) and doxorubicin + Q94 (doxorubicin at 15 mg/kg and the PAR-1 antagonist Q94 at 5 mg/kg/d) groups. Where indicated, doxorubicin was administered intravenously and PAR-1 antagonist or saline vehicle by subcutaneous osmotic mini-pump. PAR-1 expression was increased in glomeruli of mice treated with doxorubicin. Q94 treatment significantly suppressed the increased albuminuria in these nephropathic mice. Pathological analysis showed that Q94 treatment significantly attenuated periodic acid-Schiff and desmin staining, indicators of podocyte injury, and also decreased glomerular levels of podocin and nephrin. Furthermore, thrombin increased intracellular calcium levels in podocytes. This increase was suppressed by Q94 and Rox4560, a transient receptor potential cation channel (TRPC) 3/6 antagonist. In addition, both Q94 and Rox4560 suppressed the doxorubicin-induced increase in activities of caspase-9 and caspase-3 in podocytes. These data suggested that PAR-1 contributes to development of podocyte and glomerular injury and that PAR-1 antagonists have therapeutic potential. (C) 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.