Protease-activated receptor-2 (PAR2), which belongs to a specific class of the G-protein-coupled receptors, is central to several inflammation processes. However, the precise molecular mechanism involved remains undefined. Autophagy has been previously shown to affect inflammation. In the present study, we examine the effect of PAR2 on kidney tubular epithelial autophagy and on autophagy-related inflammation and reveal the underlying mechanism involved. Autophagic activity and levels of autophagic marker LC3 were examined in human kidney tubular epithelial cells with PAR2 knockdown or overexpression. We administered the mammalian target of rapamycin (mTOR) inhibitor (rapamycin) or activator (MHY1485) to investigate the function of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. We also used transforming growth factor-β1 (TGF-β1)-induced HK-2 cell inflammation models to investigate the role of PAR2-associated autophagy in kidney tubular epithelial inflammation. PAR2 antagonist and rapamycin were administered to mice after unilateral ureteral obstruction to detect the correlations between PAR2, autophagy, and inflammation. Our results show that PAR2 overexpression in HK-2 cells led to a greater reduction in autophagy via the PI3K/Akt/mTOR pathway activation and induces autophagy-related inflammation. Meanwhile, a knockdown of PAR2 via PAR2 RNAi transfection greatly increased autophagy and alleviated autophagy-associated inflammation. In unilateral ureteral obstruction (UUO) kidneys, PAR2 antagonist treatment greatly attenuated renal inflammation and interstitial injury by enhancing autophagy. Moreover, inhibition of mTOR, rapa, markedly increased autophagy and inhibited the UUO-induced inflammation. We conclude that PAR2 induces kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Our results are suggestive that PAR2 inhibition may play a role in the treatment of diseases with increased inflammatory responses in renal systems.
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August 2017
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The distribution of haemagglutinin (green) and β-catenin (red) in MDCK cells overexpressing Akt1-HA. In this issue of the Biochemical Journal, Castañeda et al. report on the suppression of Akt/β-catenin-mediated cell proliferation by the the inhibition of 14-3-3ζ expression (see pages 2679–2689).
Research Article|
August 02 2017
Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway
Chunyang Du;
Chunyang Du
*
1Department of Pathology, Hebei Medical University, Shijiazhuang, China
2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China
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Tao Zhang;
Tao Zhang
*
3Department of Nephrology, The Third Affiliated Hospital of Hebei Mecial University, Shijiazhuang, China
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Xia Xiao;
Xia Xiao
1Department of Pathology, Hebei Medical University, Shijiazhuang, China
2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China
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Yonghong Shi;
Yonghong Shi
1Department of Pathology, Hebei Medical University, Shijiazhuang, China
2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China
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Huijun Duan;
Huijun Duan
1Department of Pathology, Hebei Medical University, Shijiazhuang, China
2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China
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Yunzhuo Ren
1Department of Pathology, Hebei Medical University, Shijiazhuang, China
2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China
Correspondence: Yunzhuo Ren (renyunzhuo1978@163.com)
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Publisher: Portland Press Ltd
Received:
April 11 2017
Revision Received:
June 17 2017
Accepted:
July 10 2017
Accepted Manuscript online:
July 10 2017
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (16): 2733–2747.
Article history
Received:
April 11 2017
Revision Received:
June 17 2017
Accepted:
July 10 2017
Accepted Manuscript online:
July 10 2017
Connected Content
An Expression of Concern has been published:
Expression of Concern: Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway
Citation
Chunyang Du, Tao Zhang, Xia Xiao, Yonghong Shi, Huijun Duan, Yunzhuo Ren; Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Biochem J 15 August 2017; 474 (16): 2733–2747. doi: https://doi.org/10.1042/BCJ20170272
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