13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells.
13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells.
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DOI：
10.1530/jme-11-0095
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发表时间：
2012-04
影响因子：
3.5
通讯作者：
Russell Snyder;T. Thekkumkara
中科院分区：
文献类型：
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作者：
Russell Snyder;T. Thekkumkara
尚未研究通过顺式和反式作用因子的转录抑制，其使得能够实现控制血管紧张素1型受体（如MGI数据库中所列的AT 1或AGTR 1）表达的替代方法。在以前的研究中，发现维甲酸治疗与胰岛素敏感性增强有关。在我们以前的研究中，发现AT 1的表达与细胞内葡萄糖浓度呈负相关。因此，我们假设13-顺式维甲酸（13 cRA），一种抗氧化剂，增强胰岛素敏感性葡萄糖介导的AT 1下调。在这项研究中，我们使用连续传代的大鼠肝上皮细胞。我们的研究表明，暴露于13 cRA的细胞特异性下调AT 1蛋白的剂量和时间依赖性的方式，独立于受体亲和力的任何变化。AT 1表达的下调导致AngII介导的细胞内钙释放减少，这是受体介导的细胞内信号传导的标志。与受体下调类似，我们观察到AT 1 mRNA显著减少;然而，AT 1下调独立于胰岛素敏感性葡萄糖摄取和视黄酸受体激活（RAR/RXR）。用13 cRA处理导致这些细胞中p42/p44 MAP激酶的磷酸化。随后使用MEK抑制剂PD 98059的研究阻止了13 cRA介导的AT 1下调，并恢复了AngII介导的细胞内钙反应。此外，在原代大鼠主动脉平滑肌细胞中验证了13 cRA介导的对AT 1的抑制作用。总之，我们的研究结果首次表明，13 cRA具有葡萄糖和RAR/RXR的转录抑制AT 1的独立机制，这表明其在系统中的治疗潜力，其中AT 1的表达在胰岛素敏感和不敏感的组织失调。
Transcriptional repression through cis- and trans-acting factors enabling an alternate approach to control angiotensin type 1 receptor (AT1 or AGTR1 as listed in the MGI database) expression has not been studied. In previous investigations, treatment with retinoic acid was found to be associated with enhanced insulin sensitivity. In our previous study, expression of AT1 was found to be inversely correlated with intracellular glucose concentrations. Therefore, we hypothesized that 13-cis-retinoic acid (13cRA), an antioxidant, enhances insulin-sensitive glucose-mediated down-regulation of the AT1. In this study, we used continuously passaged rat liver epithelial cells. Our study shows that cells exposed to 13cRA specifically down-regulated the AT1 protein in a dose- and time-dependent manner, independently of any change in receptor affinity. Down-regulation of the AT1 expression leads to reduced AngII-mediated intracellular calcium release, a hallmark of receptor-mediated intracellular signaling. Similarly with receptor down-regulation, we observed a significant reduction in AT1 mRNA; however, the AT1 down-regulation was independent of insulin-sensitive glucose uptake and retinoic acid receptor activation (RAR/RXR). Treatment with 13cRA resulted in phosphorylation of p42/p44 MAP kinases in these cells. Subsequent studies using MEK inhibitor PD98059 prevented 13cRA-mediated AT1 down-regulation and restored AngII-mediated intracellular calcium response. Furthermore, 13cRA-mediated inhibitory effects on AT1 were validated in primary rat aortic smooth muscle cells. In summary, our results demonstrate for the first time that 13cRA has a glucose- and RAR/RXR-independent mechanism for transcriptional inhibition of AT1, suggesting its therapeutic potential in systems in which AT1 expression is deregulated in insulin-sensitive and -insensitive tissues.