title: Feedforward activation of endothelial ENaC by high sodium.
abstract: Kidney epithelial sodium channels (ENaCs) are known to be inactivated by high sodium concentrations (feedback inhibition). Recently, the endothelial sodium channel (EnNaC) was identified to control the nanomechanical properties of the endothelium. EnNaC-dependent endothelial stiffening reduces the release of nitric oxide, the hallmark of endothelial dysfunction. To study the regulatory impact of sodium on EnNaC, endothelial cells (EA.hy926 and ex vivo mouse endothelium) were incubated in aldosterone-free solutions containing either low (130 mM) or high (150 mM) sodium concentrations. By applying atomic force microscopy-based nanoindentation, an unexpected positive correlation between increasing sodium concentrations and cortical endothelial stiffness was observed, which can be attributed to functional EnNaC. In particular, an acute rise in sodium concentration (+20 mM) was sufficient to increase EnNaC membrane abundance by 90% and stiffening of the endothelial cortex by 18%. Despite the absence of exogenous aldosterone, these effects were prevented by the aldosterone synthase inhibitor FAD286 (100 nM) or the mineralocorticoid receptor (MR)-antagonist spironolactone (100 nM), indicating endogenous aldosterone synthesis and MR-dependent signaling. Interestingly, in the presence of high-sodium concentrations, FAD286 increased the transcription of the MR by 69%. Taken together, a novel feedforward activation of EnNaC by sodium is proposed that contrasts ENaC feedback inhibition in kidney.
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Korte
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany;
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Sträter
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany;
authors.forename: Verena
authors.initials: V
authors.lastname: Drüppel
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany;
authors.forename: Hans
authors.initials: H
authors.lastname: Oberleithner
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany;
authors.forename: Pia
authors.initials: P
authors.lastname: Jeggle
authors.affiliation: Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Halle, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Grossmann
authors.affiliation: Center of Laboratory Medicine, University of Münster, Münster, Germany; and.
authors.forename: Manfred
authors.initials: M
authors.lastname: Fobker
authors.affiliation: Center of Laboratory Medicine, University of Münster, Münster, Germany; and.
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany; kusche@uni-muenster.de.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kusche-Vihrog
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000494:pharmacology*
chemical_list: D053503:Epithelial Sodium Channels; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D012964:Sodium; D019405:Cytochrome P-450 CYP11B2
keywords: EnNaC; FAD286; aldosterone; atomic force microscopy; endothelium; mineralocorticoid receptor