Epithelial sodium channels: contributions to the regulation of vascular function and blood pressure

The epithelial sodium channel (ENaC) is a sodium channel expressed in renal tubules that, by selectively allowing the transmembrane passage of sodium ions, plays a crucial role in maintaining extracellular fluid volume and regulating blood pressure. Recent data have indicated that ENaC also exists in the cells of the vascular wall and contributes to the direct regulation of vascular function and blood pressure. The expression and activation of ENaC are both known to be regulated through mineralocorticoid receptor activation and serum glucocorticoid-regulated kinase 1. In addition, insulin metabolic signaling contributes to ENaC expression and activation. Other factors, including extracellular and intracellular sodium levels, protease-specific cleavage, lipids, ubiquitination and deubiquitination, advanced glycation end products, acetylation, and N-glycosylation, also play important roles in regulating ENaC expression and function. Related to ENaC activation, a number of pathophysiological abnormalities, including heightened salt-sensitive hypertension, excessive endothelial cell stiffening, dysregulation of the endothelial glycocalyx, impaired shear stress mechanosensation, and proinflammatory responses, appear to contribute to activated ENaC-induced vascular dysfunction and hypertension. Importantly, obesity and insulin resistance are associated with these pathophysiological processes. Understanding the exact molecular mechanisms by which ENaC links vascular dysfunction to cardiovascular disease may lead to novel therapeutic interventions that address the multifaceted cardiovascular risks of vascular dysfunction and hypertension.