Histone acetyl transferases CBP and p300 are necessary for maintenance of renin cell identity and transformation of smooth muscle cells to the renin phenotype.
Histone acetyl transferases CBP and p300 are necessary for maintenance of renin cell identity and transformation of smooth muscle cells to the renin phenotype.
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DOI：
10.1152/ajpheart.00782.2011
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发表时间：
2012-06
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影响因子：
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通讯作者：
E. Pentz;Magali Cordaillat;Oscar A. Carretero;Ana E. Tucker;M. S. Sequeira Lopez;R. A. Gomez
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文献类型：
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作者：
E. Pentz;Magali Cordaillat;Oscar A. Carretero;Ana E. Tucker;M. S. Sequeira Lopez;R. A. Gomez
在对动态平衡威胁的反应中，早期表达肾素的小动脉平滑肌细胞(ASMCs)通过去分化和重新表达肾素来增加表达肾素的细胞数量，从而增加循环肾素的数量。然而，控制肾素表型维持和重新获得的机制还不是很清楚。CAMP途径对肾素的合成和释放很重要：cAMP反应元件结合蛋白及其共激活子CBP和p300与肾素启动子中的cAMP反应元件结合是介导转录效应的途径。我们以前已经证明，肾素细胞中CBP和p300(CKO)有条件缺失的小鼠在成年生活中肾素表达严重减少。在这项研究中，我们调查了CKO中肾素表达细胞的丢失时间，发现在出生后肾脏分化完成后，肾素表达的丢失变得明显。为了确定CBP/p300是否是重新表达肾素所必需的，我们让CKO小鼠接受低钠饮食+卡托普利诱导aSMC向肾素表型的再转化。CKO组小鼠循环肾素水平未见升高，肾素基因和蛋白表达较对照组显著降低，仅有少数血管平滑肌细胞重新表达肾素。这些研究强调了CREB/CBP/p300复合体对于肾素细胞保持细胞记忆和重新获得肾素表达的能力至关重要，肾素表达是一种基本的生存机制，以应对动态平衡的威胁。
In response to a homeostatic threat circulating renin increases by increasing the number of cells expressing renin by dedifferentiation and re-expression of renin in arteriolar smooth muscle cells (aSMCs) that descended from cells that expressed renin in early life. However, the mechanisms that govern the maintenance and reacquisition of the renin phenotype are not well understood. The cAMP pathway is important for renin synthesis and release: the transcriptional effects are mediated by binding of cAMP responsive element binding protein with its co-activators, CBP and p300, to the cAMP response element in the renin promoter. We have shown previously that mice with conditional deletion of CBP and p300 (cKO) in renin cells had severely reduced renin expression in adult life. In this study we investigated when the loss of renin-expressing cells in the cKO occurred and found that the loss of renin expression becomes evident after differentiation of the kidney is completed during postnatal life. To determine whether CBP/p300 is necessary for re-expression of renin we subjected cKO mice to low sodium diet + captopril to induce retransformation of aSMCs to the renin phenotype. The cKO mice did not increase circulating renin, their renin mRNA and protein expression were greatly diminished compared with controls, and only a few aSMCs re-expressed renin. These studies underline the crucial importance of the CREB/CBP/p300 complex for the ability of renin cells to retain their cellular memory and regain renin expression, a fundamental survival mechanism, in response to a threat to homeostasis.