Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1) via recruitment of histone deacetylase 1 corepressor complex.
Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1) via recruitment of histone deacetylase 1 corepressor complex.
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无嘌呤/无嘧啶核酸内切酶 1 (APE1/Ref-1) 通过招募组蛋白脱乙酰酶 1 辅阻遏物复合物对小鼠肾素基因进行调节。
DOI：
10.1097/hjh.0b013e3283525124
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发表时间：
2012
影响因子：
4.9
通讯作者：
Bhakat,KishorK
中科院分区：
文献类型：
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作者：
Sengupta,Shiladitya;Chattopadhyay,Ranajoy;Mantha,AnilK;Mitra,Sankar;Bhakat,KishorK
目的：无嘌呤/无嘧啶核酸内切酶1（APE 1）杂合子小鼠具有慢性高血压。用于维持血压的肾素-血管紧张素（ANG）系统的肾素调节血管活性激素ANG II的产生。肾肾小球细胞的肾素表达和分泌受细胞内钙离子的调节。我们在这项研究中的目的是探讨APE 1的调节作用，在renin express.Methods：钙介导的调节肾素表达的APE 1的效果进行了检查，通过实时逆转录酶-PCR，Western分析和肾素启动子依赖的荧光素酶活性APE 1敲低，APE 1过表达或控制小鼠肾脏As 4。1细胞。此外，免疫共沉淀和染色质免疫沉淀试验被用来检查协会的APE 1与组蛋白去乙酰化酶（HDAC）1辅阻遏复合物和他们的招聘肾素增强子。最后，肾肾素mRNA水平和血浆肾素活性测定在野生型和APE 1-杂合子小鼠。结果：在这里，我们表明，APE 1参与钙介导的抑制肾素基因。我们的研究结果进一步表明，APE 1是HDAC 1辅阻遏复合物的一个组成部分结合到肾素增强子区域。细胞内钙离子浓度的增加增强了APE 1与HDAC 1辅阻遏物复合物的结合及其向增强子区域的募集。此外，APE 1的N-末端区域对于增强子结合辅阻遏物复合物的形成和募集至关重要。增加肾脏中的肾素表达和更高的血浆肾素活性在APE 1杂合子小鼠进一步支持APE 1的corepressor作用在vivo.Conclusion：这项研究揭示了APE 1的功能作为一种新的负调节肾素表达，从而在血压维持。
Objectives:Apurinic/apyrimidinic-endonuclease 1 (APE1) heterozygous mice have chronically elevated blood pressure. Renin of the renin–angiotensin (ANG) system for blood pressure maintenance regulates production of ANG II, a vasoactive hormone. Renin expression and secretion from kidney juxtaglomerular cells are regulated by intracellular calcium. Our objective in this study is to investigate APE1's regulatory role in renin expression.Methods:Effect of APE1 on calcium-mediated modulation of renin expression was examined by real-time reverse transcriptase-PCR, Western analysis and renin promoter-dependent luciferase activity in APE1-knockdown, APE1-overexpressing or control mouse kidney As4. 1 cells. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation assays were utilized to examine the association of APE1 with histone deacetylase (HDAC) 1 corepressor complex and their recruitment to renin enhancer. Finally, kidney renin mRNA level and plasma–renin activity were measured in wild-type and APE1-heterozygous mice.Results:Here we show that APE1 is involved in calcium-mediated repression of renin gene. Our results further indicate that APE1 is a component of HDAC1 corepressor complex bound to renin-enhancer region. Increase in intracellular calcium ion concentration enhances the association of APE1 with HDAC1 corepressor complex and their recruitment to the enhancer region. Furthermore, APE1's N-terminal region is critical for formation and recruitment of the enhancer-bound corepressor complex. Increased renin expression in kidneys and higher plasma–renin activity in APE1 heterozygous mice further supports APE1's corepressor role in vivo.Conclusion:This study uncovers APE1's function as a novel negative regulator of renin expression, and thereby in blood pressure maintenance.