The Epithelial Sodium Channel—An Underestimated Drug Target

Abstract

Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.

Dendritic cell epithelial sodium channel induced inflammation and salt-sensitive hypertension

“…Various ENaC gene mutations have been identified in individuals with inherited forms of hypertension and hypokalaemia, known as Liddle syndrome (described by Grant Liddle at Vanderbilt University). These mutations disrupt interactions between the ENaC β or γ-subunit and ubiquitin ligase, resulting in increased channel expression at the plasma membrane and increased probability of channel opening [ 53 ]. Conversely, loss-of-function mutations in α, β, and γ genes lead to pseudo-hypoaldosteronism type 1, characterized by hypotension and hyperkalaemia [ 54 ].…”

Glycocalyx–Sodium Interaction in Vascular Endothelium

“…Other substitutes that have been used in the reduction in dietary NaCl intake include yeast extract, taste peptides, and odor compounds [ 136 ]. Since the ENaC subunits are expressed in several vascular beds including mesenteric, cerebral, and renal [ 137 , 138 , 139 ], where the increased ENaC expression is also associated with salt-sensitive hypertension by causing endothelial dysfunction or vascular smooth muscle activation [ 103 , 140 ], it is a therapeutic target to be blocked using drugs such as benzamil or amiloride in conjunction with other potential anti-hypertensive agents [ 141 ]. Because high extracellular salt concentration increases ENaC expression [ 90 , 142 ], it is logical that blocking it with amiloride helps to restore endothelial function through increased phosphorylation of endothelial nitric oxide synthase (eNOS) [ 138 ].…”

Select amino acids recover cytokine-altered ENaC function in human bronchial epithelial cells

“…Reabsorption of sodium through ENaC is a major element in the regulation of extracellular fluid, and disruptions in ENaC function have been associated with various airway diseases, including cystic fibrosis, allergic rhinitis, asthma, pulmonary edema, and acute lung injury [ 6 ]. Considering the need for rapid and dynamic adjustments in ion and water movement, ENaC activity is meticulously controlled by a myriad of factors, including circulating hormones, metabolic alterations or inflammatory stimuli that affect cytoskeleton, proteolytic cleavage, trafficking, membrane stability, and proteasomal degradation [ 7 – 12 ]. In humans, ENaC consists of four homologous subunits α, β, γ and δ, arranged in a configuration of α-β-γ or δ-β-γ.…”