Chen Lihe, Zhang Xi, Zhang Wenzheng
Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas, USA.
Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas, USA.
Vitam Horm. 2015;98:101-35. doi: 10.1016/bs.vh.2014.12.004. Epub 2015 Feb 14.
Aldosterone is a major regulator of Na(+) absorption and acts primarily by controlling the epithelial Na(+) channel (ENaC) function at multiple levels including transcription. ENaC consists of α, β, and γ subunits. In the classical model, aldosterone enhances transcription primarily by activating mineralocorticoid receptor (MR). However, how aldosterone induces chromatin alternation and thus leads to gene activation or repression remains largely unknown. Emerging evidence suggests that Dot1a-Af9 complex plays an important role in repression of αENaC by directly binding and modulating targeted histone H3 K79 hypermethylation at the specific subregions of αENaC promoter. Aldosterone impairs Dot1a-Af9 formation by decreasing expression of Dot1a and Af9 and by inducing Sgk1, which, in turn, phosphorylates Af9 at S435 to weaken Dot1a-Af9 interaction. MR counterbalances Dot1a-Af9 action by competing with Dot1a for binding Af9. Af17 derepresses αENaC by competitively interacting with Dot1a and facilitating Dot1a nuclear export. Consistently, MR(-/-) mice have impaired ENaC expression at day 5 after birth, which may contribute to progressive development of pseudohypoaldosteronism type 1 in a later stage. Af17(-/-) mice have decreased ENaC expression, renal Na(+) retention, and blood pressure. In contrast, Dot1l(AC) mice have increased αENaC expression, despite a 20% reduction of the principal cells. This chapter reviews these findings linking aldosterone action to ENaC transcription through chromatin modification. Future direction toward the understanding the role of Dot1a-Af9 complex beyond ENaC regulation, in particular, in renal fibrosis is also briefly discussed.
醛固酮是钠（Na⁺）重吸收的主要调节因子，主要通过在包括转录在内的多个水平控制上皮钠通道（ENaC）功能发挥作用。ENaC由α、β和γ亚基组成。在经典模型中，醛固酮主要通过激活盐皮质激素受体（MR）来增强转录。然而，醛固酮如何诱导染色质改变从而导致基因激活或抑制在很大程度上仍不清楚。新出现的证据表明，Dot1a-Af9复合物通过直接结合并调节αENaC启动子特定亚区域的靶向组蛋白H3 K79高甲基化，在抑制αENaC方面发挥重要作用。醛固酮通过降低Dot1a和Af9的表达以及诱导Sgk1来损害Dot1a-Af9的形成，而Sgk1又会在S435位点使Af9磷酸化，从而削弱Dot1a-Af9的相互作用。MR通过与Dot1a竞争结合Af9来抵消Dot1a-Af9的作用。Af17通过与Dot1a竞争性相互作用并促进Dot1a核输出，从而解除对αENaC的抑制。同样，MR基因敲除（MR(-/-)）小鼠在出生后第5天ENaC表达受损，这可能在后期导致1型假性醛固酮增多症的进行性发展。Af17基因敲除（Af17(-/-)）小鼠的ENaC表达降低、肾钠潴留和血压下降。相反，Dot1l(AC)小鼠尽管主细胞减少了20%，但其αENaC表达增加。本章综述了这些将醛固酮作用与通过染色质修饰的ENaC转录联系起来的研究结果。还简要讨论了未来在理解Dot1a-Af9复合物在ENaC调节之外，特别是在肾纤维化中的作用方面的研究方向。
