Epigenetics and the control of the collecting duct epithelial sodium channel.
Epigenetics and the control of the collecting duct epithelial sodium channel.
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DOI：
10.1016/j.semnephrol.2013.05.010
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发表时间：
2013-07
影响因子：
3.3
通讯作者：
Kone, Bruce C.
中科院分区：
文献类型：
--
作者：
Kone, Bruce C.
顶膜上皮Na+通道亚基（ENaC）与基底侧Na+/K+- atp酶串联，介导收集管Na+再吸收。醛固酮诱导α - ENaC基因转录，这似乎限制了ENaC在该片段的活性。虽然这种反应长期以来被认为仅仅是配体核激素受体反式激活αENaC的结果，但最近已经描述了αENaC在集管中基础和醛固酮诱导的转录的表观遗传控制。这些表观遗传途径包括针对αENaC启动子特定亚区的动态核抑制因子复合物，包括端粒沉默的组蛋白甲基转移酶干扰物（Dot）1a，转录因子Af9或nadd依赖性蛋白去乙酰化酶Sirt1，关键的共调节蛋白，包括血清和糖皮质激素诱导的激酶（Sgk1）和推测的转录因子Af17，以及靶向染色质修饰。这些复合物通过Dot1a的作用，维持与αENaC启动子相关的染色质处于稳定的高甲基化状态，在基础条件下抑制αENaC的转录。醛固酮和Sgk1本身在很大程度上通过破坏或减少Dot1a-Af9和Dot1a-Sirt1复合物及其对染色质的影响来激活αENaC转录。小鼠模型显示Dot1a通路在肾盐排泄和高血压中的潜在作用。
The apical membrane epithelial Na+ channel subunit (ENaC) in series with the basolateral Na+/K+-ATPase mediates collecting duct Na+ reabsorption. Aldosterone induces αENaC gene transcription, which appears to be rate limiting for ENaC activity in this segment. While this response has long been assumed to be solely the result of liganded nuclear hormone receptors trans-activating αENaC, epigenetic controls of basal and aldosterone-induced transcription of αENaC in the collecting duct have recently been described. These epigenetic pathways involve dynamic nuclear repressor complexes targeted to specific subregions of the αENaC promoter and consisting of the histone methyltransferase disrupter of telomeric silencing (Dot)1a together with the transcriptional factor Af9 or the NAD-dependent protein deacetylase Sirt1, key co-regulatory proteins, including serum- and glucocorticoid-induced kinase (Sgk1) and the putative transcription factor Af17, and targeted chromatin modifications. The complexes, through the action of Dot1a, maintain chromatin associated with the αENaC promoter in a stable hypermethylated state, constraining αENaC transcription under basal conditions. Aldosterone and Sgk1, itself, activate αENaC transcription in large part by disrupting or diminishing the Dot1a–Af9 and Dot1a–Sirt1 complexes and their effects on chromatin. Mouse models indicate potential roles of the Dot1a pathways in renal salt excretion and hypertension.
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DOI：
10.1073/pnas.96.5.2514
发表时间：
1999-03-02
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
4.8
作者：
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