Epithelial Sodium Channel and Salt-Sensitive Hypertension

Abstract

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

Keywords: blood pressure; endothelium; extracellular fluid; nephrons; smooth muscle; sodium.

Figure 1.. Regulation of ENaC in the normal and salt-sensitive kidney

The top panel, A, illustrates several mechanisms responsible for ENaC regulation in the kidney. ENaC open probability and activity is regulated by shear stress, proteolytic cleavage, palmitoylation (indicated by blue cytoplasmic arrowheads), and extracellular [Na⁺]. Nedd4–2 facilitates ENaC ubiquitination and endocytosis. Aldosterone activates MR, increasing transcription of αENaC and the regulatory kinase Sgk1. However, in the salt sensitive kidney, panel B, MR is activated by the GTPase Rac1, independent of aldosterone. Rac1 also increases ROS production via NOX, which activates ENaC. Increased proteolytic activation of ENaC has also been reported, however, further work is needed to establish which proteases may be responsible.

Figure 2.. EnENaC limits NO production in the setting of high [Na⁺] and aldosterone

ECs have a thick surface glycocalyx that limits the availability of Na⁺ for ENaC-dependent Na⁺ transport. The glycocalyx also enhances the endothelial response to shear stress, inducing an increase in intracellular Ca²⁺, activation of eNOS, NO production and vasodilation. Increased extracellular [Na⁺] leads to glycocalyx breakdown and enhanced Na⁺ entry via ENaC. An increase in the intracellular [Na⁺] stabilizes F-actin filaments, increasing the density of the cortical cytoskeleton and limiting cellular deformation. This events inhibit eNOS and NO production, leading to vascular dysfunction. Activation of MR by aldosterone in ECs increases ENaC expression, stabilizing the cytoskeleton and reducing deformability.

Figure 3.. ENaC-dependent Na⁺ transport promotes DC activation and inflammation

ENaC-dependent Na⁺ transport in DCs triggers an influx of Ca²⁺ via the Na⁺-Ca²⁺ exchanger (NCX), leading to phosphorylation of the p47phox subunit of NOX, facilitating NOX assembly and production of ROS, and creation of IsoLG adducts. DCs with IsoLG-modified surface proteins activate T cells, leading to release of pro-inflammatory cytokines interferon gamma, and IL-17.