Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension.
Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension.
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膳食芹菜素激活 TRPV4 可拮抗醋酸脱氧皮质酮 (DOCA) 盐诱导的高血压中的肾纤维化
DOI：
10.1042/cs20160780
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Zhu Zhiming
中科院分区：
文献类型：
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作者：
Wei Xing;Gao Peng;Pu Yunfei;Li Qiang;Yang Tao;Zhang Hexuan;Xiong Shiqiang;Cui Yuanting;Li Li;Ma Xin;Liu Daoyan;Zhu Zhiming
高血压诱导的肾纤维化有助于慢性肾脏疾病的进展，芹菜素是芹菜中丰富的抗高血压黄酮，可作为瞬时受体电位香草酸4（TRPV 4）的激动剂。然而，芹菜素是否减少高血压引起的肾纤维化，以及潜在的机制，仍然难以捉摸。在本研究中，在雄性Sprague-Dawley大鼠中建立乙酸脱氧皮质酮（DOCA）-盐高血压模型，用芹菜素或溶剂处理4周。芹菜素可显著减轻DOCA盐对肾脏的结构和功能损伤，并伴有转化生长因子-β1（TGF-β1）/Smad 2/3信号通路和细胞外基质蛋白表达的降低。免疫组化、细胞贴附膜片钳和荧光钙离子成像结果表明，TRPV 4在肾脏和肾细胞中表达并被芹菜素激活。重要的是，在小鼠中敲除TRPV 4消除了在DOCA-盐高血压大鼠中观察到的芹菜素的有益作用。此外，芹菜素通过激活TRPV 4直接抑制不同肾组织中TGF-β1/Smad 2/3信号通路的激活，而与促纤维化刺激的类型无关。此外，TRPV 4介导的细胞内Ca 2+内流激活了AMP激活蛋白激酶（AMPK）/沉默调节蛋白1（SIRT 1）信号通路，从而抑制了TGF-β1/Smad 2/3信号通路。综上所述，膳食芹菜素通过TRPV 4介导的AMPK/SIRT 1激活和TGF-β1/Smad 2/3信号通路抑制对高血压诱导的肾纤维化具有有益作用。这项工作表明，膳食芹菜素可能是一个有前途的生活方式的改变，为预防高血压引起的肾损害的人群，消费高钠饮食。
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.