A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy
URI | http://shark.lib.kagawa-u.ac.jp/kuir/metadata/28450 | ||||||
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Title |
A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy
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Description |
Abstract 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. KEYWORDS: Kidney injury; Podocyte; Protease-activated receptor-1; Transient receptor potential cation channel (医博甲679) |
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Author |
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Publication Title |
Journal of Pharmacological Sciences
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Publication Title Alternative |
J Pharmacol Sci.
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Volume |
135
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Issue |
2
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Start Page |
81
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End Page |
88
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Publisher |
Japanese Pharmacological Society
日本薬理学会
Elsevier
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Publisher Aalternative |
日本薬理学会
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Published Date |
2017-09-14
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ISSN |
1347-8613
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NCID |
AA11806667
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PMID |
29110957
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DOI |
10.1016/j.jphs.2017.09.002
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Resource Type |
Thesis or Dissertation
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Language |
eng
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Relation |
出版社版DOIリンク(URL): https://doi.org/10.1016/j.jphs.2017.09.002
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Resource URL |
https://doi.org/10.1016/j.jphs.2017.09.002
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Rights |
Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.
Creative Commons Attribution Non-Commercial No-Derivatives 4.0 International License (CC-BY-NC-ND 4.0).
https://doi.org/10.1016/j.jphs.2017.09.002
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Text Version |
ETD
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Grant ID |
博甲第679号
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Grant Date |
2018-03-24
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Degree Name |
博士(医学)
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Grantor |
香川大学
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Set |
香川大学
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