Hypertension-induced renal fibrosis contributes to the progression of chronic kidney disease, and apigenin, an anti-hypertensive flavone that is abundant in celery, acts as an agonist of transient receptor potential vanilloid 4 (TRPV4). However, whether apigenin reduces hypertension-induced renal fibrosis, as well as the underlying mechanism, remains elusive. In the present study, the deoxycorticosterone acetate (DOCA)–salt hypertension model was established in male Sprague-Dawley rats that were treated with apigenin or vehicle for 4 weeks. Apigenin significantly attenuated the DOCA–salt-induced structural and functional damage to the kidney, which was accompanied by reduced expression of transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling pathway and extracellular matrix proteins. Immunochemistry, cell-attached patch clamp and fluorescent Ca2+ imaging results indicated that TRPV4 was expressed and activated by apigenin in both the kidney and renal cells. Importantly, knockout of TRPV4 in mice abolished the beneficial effects of apigenin that were observed in the DOCA–salt hypertensive rats. Additionally, apigenin directly inhibited activation of the TGF-β1/Smad2/3 signaling pathway in different renal tissues through activation of TRPV4 regardless of the type of pro-fibrotic stimulus. Moreover, the TRPV4-mediated intracellular Ca2+ influx activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway, which inhibited the TGF-β1/Smad2/3 signaling pathway. In summary, dietary apigenin has beneficial effects on hypertension-induced renal fibrosis through the TRPV4-mediated activation of AMPK/SIRT1 and inhibition of the TGF-β1/Smad2/3 signaling pathway. This work suggests that dietary apigenin may represent a promising lifestyle modification for the prevention of hypertension-induced renal damage in populations that consume a high-sodium diet.
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Research Article|
March 17 2017
Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)–salt-induced hypertension
Xing Wei;
Xing Wei
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Peng Gao;
Peng Gao
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Yunfei Pu;
Yunfei Pu
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Qiang Li;
Qiang Li
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Tao Yang;
Tao Yang
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Hexuan Zhang;
Hexuan Zhang
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Shiqiang Xiong;
Shiqiang Xiong
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Yuanting Cui;
Yuanting Cui
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Li Li;
Li Li
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Xin Ma;
Xin Ma
2Department of Drug Design and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China
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Daoyan Liu;
Daoyan Liu
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
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Zhiming Zhu
1Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Correspondence: Zhiming Zhu ([email protected])
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Publisher: Portland Press Ltd
Received:
October 09 2016
Revision Received:
December 22 2016
Accepted:
January 31 2017
Accepted Manuscript online:
January 31 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (7): 567–581.
Article history
Received:
October 09 2016
Revision Received:
December 22 2016
Accepted:
January 31 2017
Accepted Manuscript online:
January 31 2017
Citation
Xing Wei, Peng Gao, Yunfei Pu, Qiang Li, Tao Yang, Hexuan Zhang, Shiqiang Xiong, Yuanting Cui, Li Li, Xin Ma, Daoyan Liu, Zhiming Zhu; Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)–salt-induced hypertension. Clin Sci (Lond) 1 April 2017; 131 (7): 567–581. doi: https://doi.org/10.1042/CS20160780
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