The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice
The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice
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DOI：
10.1172/jci36908
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发表时间：
2009-08-01
影响因子：
15.9
通讯作者：
Wingo, Charles S.
中科院分区：
文献类型：
--
作者：
Gumz, Michelle L.;Stow, Lisa R.;Wingo, Charles S.
盐皮质激素。醛固酮是靶上皮中钠转运的主要调节剂，并有助于控制血压和心功能。它的特殊功能是通过调节上皮钠通道的α亚基（α ENaC）来增加肾对小管液体中钠的吸收。我们之前利用微阵列技术在小鼠髓内集管细胞系中鉴定了醛固酮的直接转录靶点，发现诱导程度最大的转录物是生物钟基因周期1。在这里，我们研究了周期1在肾细胞中介导醛固酮下游作用的作用。醛固酮刺激肾收集管细胞系和肾组织中Per1 mRNA的表达。在醛固酮存在或不存在的情况下，第1周期RNA沉默显著降低编码α ENaC的mRNA的表达。此外，在Per1基因被破坏的小鼠肾髓质中，α - enact编码mRNA的表达减弱，这些小鼠表现出尿钠排泄增加。肾α - enac编码mRNA以明显的昼夜节律模式表达，而这种模式在缺乏功能周期基因的小鼠中显著改变。这些结果表明，周期1在调节肾上皮钠通道中的作用，更广泛地说，生物钟在控制钠平衡中起作用。
The mineralocorticoid. aldosterone is a major regulator of sodium transport in target epithelia and contributes to the control of blood pressure and cardiac function. It specifically functions to increase renal absorption of sodium from tubular fluid via regulation of the alpha subunit of the epithelial sodium channel (alpha ENaC). We previously used microarray technology to identify the immediate transcriptional targets of aldosterone in a mouse inner medullary collecting duct cell line and found that the transcript induced to the greatest extent was the circadian clock gene Period 1. Here, we investigated the role of Period 1 in mediating the downstream effects of aldosterone in renal cells. Aldosterone treatment stimulated expression of Period 1 (Per1) mRNA in renal collecting duct cell lines and in the rodent kidney. RNA silencing of Period 1 dramatically decreased expression of mRNA encoding alpha ENaC in the presence or absence of aldosterone. Furthermore, expression of alpha ENaC-encoding mRNA was attenuated in the renal medulla of mice with disruption of the Per1 gene, and these mice exhibited increased urinary sodium excretion. Renal alpha ENaC-encoding mRNA was expressed in an apparent circadian pattern, and this pattern was dramatically altered in mice lacking functional Period genes. These results suggest a role for Period 1 in the regulation of the renal epithelial sodium channel and more broadly implicate the circadian clock in control of sodium balance.