Effect of SARS-CoV-2 S protein on the proteolytic cleavage of the epithelial Na+ channel ENaC.

Severe cases of COVID-19 are characterized by development of acute respiratory distress syndrome (ARDS). Water accumulation in the lungs is thought to occur as consequence of an exaggerated inflammatory response. A possible mechanism could involve decreased activity of the epithelial Na+ channel, ENaC, expressed in type II pneumocytes. Reduced transepithelial Na+ reabsorption could contribute to lung edema due to reduced alveolar fluid clearance. This hypothesis is based on the observation of the presence of a novel furin cleavage site in the S protein of SARS-CoV-2 that is identical to the furin cleavage site present in the alpha subunit of ENaC. Proteolytic processing of αENaC by furin-like proteases is essential for channel activity. Thus, competition between S protein and αENaC for furin-mediated cleavage in SARS-CoV-2-infected cells may negatively affect channel activity. Here we present experimental evidence showing that coexpression of the S protein with ENaC in a cellular model reduces channel activity. In addition, we show that bidirectional competition for cleavage by furin-like proteases occurs between 〈ENaC and S protein. In transgenic mice sensitive to lethal SARS-CoV-2, however, a significant decrease in gamma ENaC expression was not observed by immunostaining of lungs infected as shown by SARS-CoV2 nucleoprotein staining.

Role of NCC in the pathophysiology of hypertension in primary aldosteronism.

PURPOSE OF REVIEW: An increasing amount of evidence points out to a role for the thiazide-sensitive Na+:Cl- cotransporter, NCC, in the blood pressure alterations observed in conditions of pathologically high or pathologically low aldosterone. Here, we briefly review this evidence that is changing our perception of the pathophysiology of primary aldosteronism. RECENT FINDINGS: Although initially NCC was thought to be a direct target of aldosterone, more recent evidence suggests that NCC is only indirectly regulated by aldosterone, at least in a chronic setting. Aldosterone-induced changes in plasma K+ concentration that are prompted by the modulation of K+ secretion in principal cells of the connecting tubule and collecting duct are actually responsible for the modulation of NCC in conditions of altered aldosterone levels. A mounting amount of evidence suggests that this indirect effect of aldosterone on NCC may be key to produce the blood pressure alterations observed in aldosterone excess or aldosterone deficit. Finally, recent insights into the molecular pathways involved in NCC modulation by K+ are briefly reviewed. SUMMARY: The evidence reviewed here suggests that correction of K+ alterations in patients with hyper or hypoaldosteronism may substantially affect blood pressure levels. Mechanistically, this may be related to the K+-mediated modulation of NCC.