Endothelial cell serum and glucocorticoid regulated kinase 1 (SGK1) mediates DOCA-salt-induced endothelial cell and arterial stiffening
Authors: Zhang Liping , Zhe Sun , Mack Austin , Sowers James , Hill Micael 
Published: May 2023

Introduction: Vascular stiffening is an independent predictor of cardiovascular diseases, the leading cause of death worldwide. High dietary salt intake has been shown to increase vascular stiffness in humans, especially in salt-sensitive populations. To date, the underlying mechanisms of high salt-induced vascular stiffening remain poorly understood. Our recent study used the deoxycortisone acetate (DOCA)-salt mouse model, which exhibits increased mineralocorticoid levels, and thus replicates a situation of high salt consumption in salt-sensitive humans who do not manifest appropriate suppression of aldosterone production. Our data has revealed a vital role of the endothelial sodium channel (EnNaC) in salt-sensitivity-related endothelial cell (EC) and arterial stiffening. Nevertheless, the exact mechanisms by which DOCA-salt activate EnNaC and cause EC and arterial stiffening are yet to be determined. Further, related studies in renal epithelial cells have shown that SGK1 is a key regulator of sodium channel activity. Thus, in the current study, we hypothesized that EC-SGK1 mediates DOCA-salt-induced EC and arterial stiffening. Methods: To probe signaling pathways, we produced a mouse model with specific deletion of EC-SGK1 by cross-breeding cadherin 5-Cre mice with sgk1flox/flox mice. The knockout model was validated by genotyping PCR and quantitative PCR. Further, littermate control and EC-SGK1 knockout mice underwent either a sham surgery or were implanted, subcutaneously, with slow-release DOCA pellets (100mg) and given salt (1% NaCl, 0.2% KCl) in their drinking water for 42 days. Blood pressures and pulse wave velocity (PWV) were measured immediately prior to initiating treatments and at the end of the study using tail-cuff and ultrasound, respectively. Thoracic aortae were freshly isolated for measurement of aortic EC stiffness by atomic force microscopy. Results: SGK1 mRNA levels were significantly reduced in ECs but not smooth muscle cells isolated from EC-SGK1 knockout mice as compared to those from littermate control mice. DOCA-salt treated control mice had significantly increased blood pressure which was prevented in EC-SGK1 knockout mice. DOCA-salt-induced increases in PWV and EC stiffness were significantly attenuated by EC-SGK1 deletion. Conclusion: EC-SGK1 knock out mice were successfully produced and used to suggest that EC-SGK1 plays a role in salt-sensitivity related EC and arterial stiffening. Whether this is directly mediated through EC-SGK1 regulation of EnNaC requires further examination. We further conclude that our study may provide potential insights into approaches for developing therapeutic interventions for salt-sensitive hypertension-related cardiovascular dysfunction.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.