A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy

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URI http://shark.lib.kagawa-u.ac.jp/kuir/metadata/28450
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)

Author
著者 管 瑀
著者(ヨミ) グアン ユ
著者(別表記) Guana Yu
Publication Title
Journal of Pharmacological Sciences
Publication Title Alternative
J Pharmacol Sci.
Volume
135
Issue
2
Start Page
81
End Page
88
Publisher
Japanese Pharmacological Society
日本薬理学会
Elsevier
Publisher Aalternative
日本薬理学会
Published Date
2017-09-14
ISSN
1347-8613
NCID
AA11806667
PMID
29110957
DOI
10.1016/j.jphs.2017.09.002
Resource Type
Thesis or Dissertation
Language
eng
Relation
出版社版DOIリンク(URL): https://doi.org/10.1016/j.jphs.2017.09.002
Resource URL
https://doi.org/10.1016/j.jphs.2017.09.002
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
Text Version
ETD
Grant ID
博甲第679号
Grant Date
2018-03-24
Degree Name
博士(医学)
Grantor
香川大学
Set
香川大学
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