Epithelial Sodium Channel Stiffens the Vascular Endothelium In Vitro and in Liddle Mice
Epithelial Sodium Channel Stiffens the Vascular Endothelium In Vitro and in Liddle Mice
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DOI：
10.1161/hypertensionaha.111.199455
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发表时间：
2013-05-01
期刊：
影响因子：
8.3
通讯作者：
Kusche-Vihrog, Kristina
中科院分区：
文献类型：
--
作者：
Jeggle, Pia;Callies, Chiara;Kusche-Vihrog, Kristina
Liddle 综合征是一种遗传性高血压，是由上皮 Na+ 通道 (ENaC) 的功能获得性突变引起的，ENaC 是肾脏 Na+ 重吸收的主要介质。因此，该疾病病理学归因于原发性肾脏机制。然而，这是否是唯一的机制仍不确定，因为其他组织中的 ENaC 失调也可能参与其中。先前的研究表明，血管内皮细胞中的 ENaC 对于细胞力学乃至血管功能的调节至关重要。醛固酮激素已被证明可以同时增加血管内皮细胞中 ENaC 表面表达和细胞皮质的硬度。后者导致血管舒张剂一氧化氮的释放减少，最终导致血管张力和血压升高。使用原子力显微镜，我们发现 ENaC 表面表达与内皮细胞皮质僵硬的形成之间存在直接相关性。与模拟对照相比，内皮细胞中 α ENaC 的稳定敲低引起通道表面密度降低和皮质硬度降低。反过来，α ENaC 表达增加会导致皮质硬度升高。更重要的是，利用 Liddle 综合征小鼠模型的离体制剂，我们发现这种疾病会引起血管内皮细胞原位 ENaC 表达增强和皮质硬度增加。我们得出结论，血管内皮中的 ENaC 决定细胞力学，因此可能参与血管功能的控制。 （高血压。2013 年；61：1053-1059。）在线数据补充
Liddle syndrome, an inherited form of hypertension, is caused by gain-of-function mutations in the epithelial Na+ channel (ENaC), the principal mediator of Na+ reabsorption in the kidney. Accordingly, the disease pathology was ascribed to a primary renal mechanism. Whether this is the sole responsible mechanism, however, remains uncertain as dysregulation of ENaC in other tissues may also be involved. Previous work indicates that ENaC in the vascular endothelium is crucial for the regulation of cellular mechanics and thus vascular function. The hormone aldosterone has been shown to concomitantly increase ENaC surface expression and stiffness of the cell cortex in vascular endothelial cells. The latter entails a reduced release of the vasodilator nitric oxide, which eventually leads to an increase in vascular tone and blood pressure. Using atomic force microscopy, we have found a direct correlation between ENaC surface expression and the formation of cortical stiffness in endothelial cells. Stable knockdown of alpha ENaC in endothelial cells evoked a reduced channel surface density and a lower cortical stiffness compared with the mock control. In turn, an increased alpha ENaC expression induced an elevated cortical stiffness. More importantly, using ex vivo preparations from a mouse model for Liddle syndrome, we show that this disorder evokes enhanced ENaC expression and increased cortical stiffness in vascular endothelial cells in situ. We conclude that ENaC in the vascular endothelium determines cellular mechanics and hence might participate in the control of vascular function. (Hypertension. 2013; 61: 1053-1059.) . Online Data Supplement