title: Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension.
abstract: 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.
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wei
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Pu
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Hexuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Drug Design and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China zhuzm@yahoo.com.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D047310:Apigenin / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D064791:Desoxycorticosterone Acetate; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005355:Fibrosis; D006977:Hypertension, Renal / Q000139:chemically induced / Q000178:diet therapy* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000502:physiology; D017673:Sodium Chloride, Dietary; D050916:TRPV Cation Channels / Q000378:metabolism / Q000502:physiology*
chemical_list: D000959:Antihypertensive Agents; D017673:Sodium Chloride, Dietary; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D064791:Desoxycorticosterone Acetate; D047310:Apigenin; D055372:AMP-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D002118:Calcium
keywords: AMPK/SIRT1 pathway; TGF-β1/Smad2/3 signaling; TRPV4; apigenin; hypertension; renal fibrosis