Jeggle Pia, Hofschröer Verena, Maase Martina, Bertog Marko, Kusche-Vihrog Kristina
*Institute of Physiology II, University of Munster, Munster, Germany; and Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
*Institute of Physiology II, University of Munster, Munster, Germany; and Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
FASEB J. 2016 Jan;30(1):45-53. doi: 10.1096/fj.14-259606. Epub 2015 Aug 31.
Recently, a novel feedforward activation of the endothelial epithelial sodium channel (ENaC) [endothelial sodium channel (EnNaC)] by sodium was reported that counteracts ENaC function in kidney. In the absence of aldosterone, a rise in extracellular sodium (>145 mM) increases EnNaC surface abundance, thereby stiffening the cortex of vascular endothelial cells (ECs) in vitro. The latter reduces the release of NO-the hallmark of endothelial dysfunction. Here, we test whether high extracellular sodium per se increases EnNaC expression and cortical stiffness in an aldosterone synthase (Cyp11b2)-deficient (AS(-/-)) mouse model. Therefore, we employed in situ ECs of ex vivo aorta preparations from wild-type (WT) and AS(-/-). EnNaC surface expression (-16%) and cortical stiffness (-22%) were reduced in AS(-/-), compared with WT, whereas NO secretion was exclusively detectable in AS(-/-). EnNaC inhibition with benzamil decreased stiffness in both, while mineralocorticoid receptor antagonism diminished stiffness only in the WT. In the absence of aldosterone, high sodium (150 mM) increased EnNaC surface expression ex vivo (plus 19%) and cortical stiffness ex vivo (plus 41%) and in vivo (plus 44%). Application of aldosterone adjusted the stiffness of AS(-/-) to the WT level. We conclude that high sodium per se determines EnNaC expression and consequently endothelial cortical nanomechanics, thus likely contributing to endothelial dysfunction.
最近，有报道称钠对内皮上皮钠通道（ENaC）[内皮钠通道（EnNaC）]有一种新的前馈激活作用，这种作用会抵消肾脏中ENaC的功能。在没有醛固酮的情况下，细胞外钠浓度升高（>145 mM）会增加EnNaC的表面丰度，从而使体外血管内皮细胞（ECs）的皮质变硬。后者会减少一氧化氮（NO）的释放——这是内皮功能障碍的标志。在此，我们测试在醛固酮合酶（Cyp11b2）缺陷（AS(-/-)）小鼠模型中，高细胞外钠本身是否会增加EnNaC表达和皮质硬度。因此，我们使用了来自野生型（WT）和AS(-/-)的离体主动脉制剂中的原位ECs。与WT相比，AS(-/-)中的EnNaC表面表达（降低16%）和皮质硬度（降低22%）均降低，而仅在AS(-/-)中可检测到NO分泌。用苯甲酰胺抑制EnNaC可降低两者的硬度，而盐皮质激素受体拮抗剂仅在WT中降低硬度。在没有醛固酮的情况下，高钠（150 mM）可使体外EnNaC表面表达增加（增加19%）、体外皮质硬度增加（增加41%）以及体内皮质硬度增加（增加44%）。应用醛固酮可将AS(-/-)的硬度调整至WT水平。我们得出结论，高钠本身决定了EnNaC的表达，进而决定了内皮皮质纳米力学，因此可能导致内皮功能障碍。
