DOCA‐Salt‐Induced Endothelial Cell Stiffening Occurs Via mTORC2/SGK1 mediated Regulation of EnNaC

Objective The deoxycortisone acetate (DOCA)‐salt model of hypertension and vascular disease replicates a situation of high aldosterone and high salt consumption in humans. Moreover, mTORC2 activation has been shown to increase SGK1‐mediated activation of the epithelial Na+ channels in renal tubular epithelial cells. We hypothesized that in the DOCA‐salt model, increased mineralocorticoid receptor (MR) activation would result in increased activity of the endothelial cell (EC) sodium channel (EnNaC) via mTOR signaling and ultimately increased endothelial cell stiffness. Methods and Result Mice were implanted with slow‐released DOCA pellets and given salt (1%) in their drinking water for 21 days. To probe signaling we used mice with either specific deletion of the alpha subunit of EnNaC or treated with a pharmacological inhibitor of mTORC2 (mTI). Our data showed that DOCA‐salt treated control mice had increased blood pressure, EC Na + transport activity (Fig.1) and EC stiffness (Fig.2) which were attenuated in both the EnNaC KO and mTI‐treated groups. Further, depletion of alpha EnNaC prevented DOCA‐salt‐induced impairment in EC dependent vascular relaxation. Our preliminary data further show that global SGK1 deletion in mice prevented DOCA‐salt‐induced hypertension and increased EC Na+ transport activity. Conclusion Collectively, the data suggest that in the presence of MR activation and high salt consumption, activation of EnNaC contributes to EC stiffness and vascular relaxation. The underlying mechanisms appear to involve mTORC2/SGK1 signaling.