Abstract
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 stiffnessex 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.
| Original language | English |
|---|---|
| Journal | FASEB Journal |
| Volume | 30 |
| Issue number | 1 |
| Pages (from-to) | 45-53 |
| Number of pages | 9 |
| ISSN | 0892-6638 |
| DOIs | |
| Publication status | Published - 01.01.2016 |
Funding
The authors thank Professors Hans Oberleithner (Institute of Physiology II, University of M?nster, M?nster, Germany) and Christoph Korbmacher (Institute of Physiology, University of Erlangen, Erlangen, Germany) for their support in this study and Marianne Wilhelmi and Sergej Handel (Institute of Physiology II, University of M?nster) for their excellent work on the mouse aorta preparations. The authors are grateful to Manfred Fobker (Center of Laboratory Medicine, University of M?nster) for the quantification of the plasma aldosterone concentration. This paper is dedicated to the late Professor Hugh de Wardener (Imperial College London, London, United Kingdom), who discussed and commented on our data. This work was supported by grants from the Deutsche Forschungsgemeinschaft (KU 1496/7-1, OB 63/17-1, and Koselleck-OB 63/18), Innovative Medical Research of the University of M?nster Medical School (KU 120808), Else-Kr?ner-Fresenius Stiftung (2010 A116), and by the Centre of Excellence (Cells in Motion), University of M?nster. The authors are grateful to COST Action TD1002 as well as COST Action BM1301 for supporting networking activities. The authors declare no conflicts of interest.
