Beschreibung:
The deoxycortisone acetate (DOCA)/salt model of hypertension and vascular disease replicates a situation of high aldosterone and high salt consumption in humans. We hypothesized that in this model, increased mineralocorticoid receptor (MR) activation would result in increased activity of the endothelial cell sodium channel (EnNaC) leading to increased endothelial cell and vascular stiffness. Female and male mice were implanted with slow release DOCA pellets (50 mg) and given salt in their drinking water (1% NaCl with 0.2% KCl) for 21 days. To probe signaling pathways underlying EnNaC activation induced endothelial cell stiffness we used mice with a specific deletion of the alpha subunit of EnNaC (EnNaC KO) and mice treated with a pharmacological inhibitor of mTORC2 (PP242, 10 mg/kg/day; mTI). Indeed, mTORC2 activation has been shown to increase SGK1 mediated activation of the epithelial Na+ channels in renal epithelial cells (Gleason et al., J. Clin. Invest. 2015). DOCA-salt treated control mice showed an increase in blood pressure and aortic vascular stiffness (ECHO PW analysis) which was attenuated in both the EnNaC KO and mTI-treated groups. Similarly, DOCA-salt administration increased endothelial cell Na + transport activity as measured by whole cell patch clamp. The Na + conductance was blocked by amiloride consistent with a role for the EnNaC ion channel. Further, intrinsic endothelial cell stiffness as measured by AFM was decreased in EnNaC KO and mTI-treated mice compared to control mice given DOCA-salt, alone. Collectively, the data indicate that in the presence of MR activation and high salt consumption, that activation of EnNaC contributes to endothelial cell and vascular stiffness. This appears to involve a contribution of mTOR signaling which is known to stimulate SGK1 mediated increases in the Na + channel at the EC surface and associated increased channel activity. We further conclude that the data are relevant to situations of enhanced aldosterone secretion and MR activation in concert with high salt consumption (ie. salt sensitivitive and resistant hypertension).