Endothelial Cell Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Mediates Vascular Stiffening

Abstract

BackgroundExcess dietary salt increases vascular stiffness in humans, especially in salt- sensitive populations. While we recently suggested that the endothelial sodium channel (EnNaC) contributes to salt-sensitivity related endothelial cell (EC) and arterial stiffening, mechanistic understanding is incomplete. This study thus aimed to explore the role of EC-serum and glucocorticoid regulated kinase 1 (SGK1), as a regulator of sodium channels, in EC and arterial stiffening. Methods and ResultsA mouse model of salt sensitivity-associated vascular stiffening was produced by subcutaneous implantation of slow-release deoxycorticosterone acetate (DOCA) pellets, with salt (1% NaCl, 0.2% KCl) administered via drinking water. Preliminary data showed that global SGK1 deletion caused significantly decreased blood pressure, EnNaC activity and aortic endothelium stiffness as compared to control mice following DOCA-salt treatment. To probe EC signaling pathways, selective deletion of EC-SGK1 was performed by cross-breeding cadherin 5-Cre mice with sgk1flox/flox mice. DOCA-salt treated control mice had significantly increased blood pressure, EC and aortic stiffness in vivo and ex vivo, which were attenuated by EC-SGK1 deficiency. To demonstrate relevance to humans, human aortic ECs were cultured in the absence or presence of aldosterone and high salt with or without the SGK1 inhibitor, EMD638683 (10uM or 25uM). Treatment with aldosterone and high salt increased intrinsic stiffness of ECs, which was prevented by SGK1 inhibition. Further, the SGK1 inhibitor prevented aldosterone and high salt induced actin polymerization, a key mechanism in cellular stiffening. ConclusionEC-SGK1 mediates salt-sensitivity related EC and aortic stiffening by mechanisms appearing to involve regulation actin polymerization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/563167v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@74497forg.highwire.dtl.DTLVardef@855709org.highwire.dtl.DTLVardef@151c72org.highwire.dtl.DTLVardef@1feae92_HPS_FORMAT_FIGEXP M_FIG C_FIG