Endothelial cell serum and glucocorticoid regulated kinase 1 (SGK1) mediates vascular stiffening

Abstract

Background: Excessive dietary salt intake 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 remains incomplete. This study therefore aimed to explore the role of EC-serum and glucocorticoid regulated kinase 1 (SGK1), as a reported regulator of sodium channels, in EC and arterial stiffening.

Methods and results: A 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 (BP), 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 sgk1^flox/flox mice. DOCA-salt treated control mice had significantly increased BP, 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.

Conclusion: EC-SGK1 contributes to salt-sensitivity related EC and aortic stiffening by mechanisms appearing to involve regulation of actin polymerization.

Keywords: Endothelial cells; Mineralocorticoid receptor activation; Salt sensitivity; Serum and glucocorticoid stimulated kinase 1; Vascular stiffness.