Tannic acid down-regulates the angiotensin type 1 receptor through a MAPK-dependent mechanism.
Tannic acid down-regulates the angiotensin type 1 receptor through a MAPK-dependent mechanism.
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DOI：
10.1210/me.2011-1224
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发表时间：
2012-02
影响因子：
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通讯作者：
Rekha Yesudas;U. Gumaste;Russell Snyder;T. Thekkumkara
中科院分区：
文献类型：
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作者：
Rekha Yesudas;U. Gumaste;Russell Snyder;T. Thekkumkara
在本研究中，我们研究了单宁酸（TA），水解多酚，对血管紧张素1型受体（AT 1 R）在连续传代大鼠肝上皮细胞表达的影响。在正常条件下，细胞暴露于TA导致AT 1 R特异性结合的下调，浓度范围为12.5-100 μg/ml（7.34-58.78 μm），持续2-24 h，与血管紧张素II（AngII）的受体亲和力无变化。TA对AT 1 R的抑制作用是特异的、可逆的。在TA处理的细胞中，我们观察到AngII介导的细胞内钙信号的显著减少，这一发现与受体下调一致。在相似的条件下，TA下调AT 1 R mRNA的表达，而不改变mRNA降解的速率，表明TA的作用是通过转录抑制介导的。细胞表达重组AT 1 R没有天然启动子显示受体表达没有变化，而具有大鼠AT 1 R启动子的pCAT报告构建体的活性显着降低。此外，TA诱导MAPK p42/p44的磷酸化。用MAPK激酶（MEK）特异性抑制剂PD 98059预处理细胞可阻止TA诱导的MAPK磷酸化和AT 1 R下调。此外，MEK抑制后AngII介导的细胞内钙释放没有减少，表明TA观察到的抑制作用是通过MEK/MAPK信号转导介导的。我们的研究结果表明，第一次，TA抑制AT 1 R基因表达和细胞反应，这表明观察到的保护作用，膳食多酚对心血管疾病可能是，部分，通过抑制AT 1 R的表达。
In the present study, we investigated the effects of tannic acid (TA), a hydrolysable polyphenol, on angiotensin type 1 receptor (AT1R) expression in continuously passaged rat liver epithelial cells. Under normal conditions, exposure of cells to TA resulted in the down-regulation of AT1R-specific binding in concentrations ranging from 12.5-100 μg/ml (7.34-58.78 μm) over a time period of 2-24 h with no change in receptor affinity to angiotensin II (AngII). The inhibitory effect of TA on AT1R was specific and reversible. In TA-treated cells, we observed a significant reduction in AngII-mediated intracellular calcium signaling, a finding consistent with receptor down-regulation. Under similar conditions, TA down-regulated AT1R mRNA expression without changing the rate of mRNA degradation, suggesting that TA's effect is mediated through transcriptional inhibition. Cells expressing recombinant AT1R without the native promoter show no change in receptor expression, whereas a pCAT reporter construct possessing the rat AT1R promoter was significantly reduced in activity. Furthermore, TA induced the phosphorylation of MAPK p42/p44. Pretreatment of the cells with a MAPK kinase (MEK)-specific inhibitor PD98059 prevented TA-induced MAPK phosphorylation and down-regulation of the AT1R. Moreover, there was no reduction in AngII-mediated intracellular calcium release upon MEK inhibition, suggesting that TA's observed inhibitory effect is mediated through MEK/MAPK signaling. Our findings demonstrate, for the first time, that TA inhibits AT1R gene expression and cellular response, suggesting the observed protective effects of dietary polyphenols on cardiovascular conditions may be, in part, through inhibition of AT1R expression.