Role of transcriptional cis-elements, angiotensinogen gene-activating elements, of angiotensinogen gene in blood pressure regulation.
Role of transcriptional cis-elements, angiotensinogen gene-activating elements, of angiotensinogen gene in blood pressure regulation.
复制标题
血管紧张素原基因转录顺式元件、血管紧张素原基因激活元件在血压调节中的作用。
作者：
R. Morishita;J. Higaki;N. Tomita;Motokuni Aoki;A. Moriguchi;Kouichi Tamura;K. Murakami;Y. Kaneda;Toshio Ogihara
最近的遗传学研究结果表明，血管紧张素原基因可能是高血压的决定因素。利用反义技术，我们证明了循环血管紧张素原的产生是血压调节的限速步骤。在本研究中，我们研究了血管紧张素原基因是如何在体内调节的。转录顺式元件，血管紧张素原基因激活元件（AGE）2和3，已被报道在体外调节人肝细胞血管紧张素原的生产。为了确定体内血管紧张素原生产的关键转录调节因子，我们使用合成的双链寡脱氧核苷酸（ODN）作为“诱饵”顺式元件来阻断核因子与靶基因启动子区域的结合，从而抑制基因的反式激活。在这里，我们研究是否AGE 2和AGE 3在血管紧张素原基因的启动子区域在体内肝血管紧张素原生产中具有关键作用。AGE 2转染可降低肝血管紧张素原mRNA的表达，而错配诱骗ODN则无此作用。针对AGE 2的诱骗而非错配ODN的转染导致自发性高血压大鼠（SHR）血压的短暂降低，伴随着血浆血管紧张素原和血管紧张素II水平的降低。相反，AGE 3诱饵ODN转染对血压的影响很小.总之，我们的研究结果表明，针对AGE 2，但不是针对AGE 3，血管紧张素原基因的诱饵ODN转染导致SHR的高血压的瞬时降低，这表明转录顺式元件AGE 2，而不是AGE 3，通过控制循环血管紧张素原在血压调节中具有重要作用。
Results of recent genetic studies suggest that the angiotensinogen gene is a possible determinant of hypertension. Using antisense technology, we demonstrated that generation of circulating angiotensinogen is a rate-limiting step in blood pressure regulation. In the present study, we examined how the angiotensinogen gene is regulated in vivo. The transcriptional cis-elements, angiotensinogen gene-activating elements (AGE) 2 and 3, have been reported to regulate angiotensinogen production in human hepatocytes in vitro. To determine the critical transcriptional regulator of angiotensinogen production in vivo, we used synthetic double-stranded oligodeoxynucleotides (ODN) as "decoy" cis-elements to block the binding of nuclear factors to promoter regions of the targeted gene, resulting in the inhibition of gene transactivation. Here we examined whether AGE 2 and AGE 3 in the promoter region of the angiotensinogen gene have a pivotal role in hepatic angiotensinogen production in vivo. Hepatic angiotensinogen mRNA was decreased by the transfection of AGE 2 but not mismatched decoy ODN. Transfection of decoy but not mismatched ODN against AGE 2 resulted in a transient decrease in blood pressure of spontaneously hypertensive rats (SHR), accompanied by a reduction in plasma angiotensinogen and angiotensin II levels. In contrast, transfection of AGE 3 decoy ODN had little effect on blood pressure. Overall, our results demonstrate that transfection of decoy ODN against AGE 2, but not against AGE 3, of the angiotensinogen gene resulted in a transient decrease in high blood pressure of SHR, suggesting that the transcriptional cis-element AGE 2, rather than AGE 3, has an important role in blood pressure regulation through the control of circulating angiotensinogen.
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DOI：
10.1172/jci118156
发表时间：
1995
期刊：
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影响因子：
--
作者：
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DOI：
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发表时间：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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