Figure 4.

Pathophysiological regulation of ENaC in barrier cells, such as type II pneumocytes expressing ACE2, TMPRSS2 [48], and ENaC [49]. These cells are a validated target of SARS-CoV-2 and exhibit viral particles in all investigated post-mortem lung tissues of COVID-19 patients [50], though other barrier cells, including ileal absorptive enterocytes, ciliated cells, and nasal goblet secretory cells, can also be infected [48]. Endothelial cells express ACE2, but not TMPRSS2 in the post-mortem lung tissues from COVID-19 patients [51]. Endothelial cells do not contain SARS-CoV-2 particles [50] but exhibit osmotic malfunctions: swelling, rupture, microthrombosis, and/or necrosis in these tissues [20,50], that may involve ENaC expressed in these cells [41]. Physiological regulation of ENaC activity is facilitated via feedback mechanism. In the ‘OFF’ state of ACE2, Ang II/AT1R (green arrow) induces mobilization and expression of the αβγENaC (blue, yellow, and orange shapes) to the apical side of barrier cells. Na⁺ follows a gradient to the basolateral side where Na⁺/K⁺ ATPase transporters mediate efflux of Na⁺ into the blood in exchange for K⁺. Na⁺/K⁺ ATPase transporters, cystic fibrosis transmembrane conductance regulator (CFTR), and Na⁺-K⁺-Cl⁻ cotransporter 1 (NKCC1) are expressed in pneumocytes and regulate alveolar fluid balance [52]. This Na⁺ flow establishes a positive transcellular current (polarization) of ~2.7 ± 0.5 μA/cm². The K⁺ follows a gradient to the apical side where its efflux is mediated by multiple transporters leading to a 3–5-fold higher concentration of K⁺ in airway surface fluid (15–27 mM K⁺), compared to blood (5 mM K⁺). TMPRSS2 (orange line shape) binding inhibits ENaC; however, TMPRSS2 is suppressed by K⁺ ions bound to G quadruplex in the promoter region (nucleus). Intracellular loss of K⁺ activates TMPRSS2 expression creating a potential feedback loop for inhibition of ENaC activity. Pathological regulation. The furin cleavage site on SARS-CoV-2 is homologous to human ENaC and therefore, can provide an alternative site for binding of TMPRSS2, which can cleave SARS-CoV-2 for replication. Host’s ENaC remains activated without inhibition by TMPRSS2.