Osmotic Adaptation by Na+-Dependent Transporters and ACE2: Correlation with Hemostatic Crisis in COVID-19

Abstract

COVID-19 symptoms, including hypokalemia, hypoalbuminemia, ageusia, neurological dysfunctions, D-dimer production, and multi-organ microthrombosis reach beyond effects attributed to impaired angiotensin-converting enzyme 2 (ACE2) signaling and elevated concentrations of angiotensin II (Ang II). Although both SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus) and SARS-CoV-2 utilize ACE2 for host entry, distinct COVID-19 pathogenesis coincides with the acquisition of a new sequence, which is homologous to the furin cleavage site of the human epithelial Na+ channel (ENaC). This review provides a comprehensive summary of the role of ACE2 in the assembly of Na+-dependent transporters of glucose, imino and neutral amino acids, as well as the functions of ENaC. Data support an osmotic adaptation mechanism in which osmotic and hemostatic instability induced by Ang II-activated ENaC is counterbalanced by an influx of organic osmolytes and Na+ through the ACE2 complex. We propose a paradigm for the two-site attack of SARS-CoV-2 leading to ENaC hyperactivation and inactivation of the ACE2 complex, which collapses cell osmolality and leads to rupture and/or necrotic death of swollen pulmonary, endothelial, and cardiac cells, thrombosis in infected and non-infected tissues, and aberrant sensory and neurological perception in COVID-19 patients. This dual mechanism employed by SARS-CoV-2 calls for combinatorial treatment strategies to address and prevent severe complications of COVID-19.

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“…It is considered an early event in the pathophysiology of CV disease, contributing to subclinical target organ damage [ 25 , 26 ]. Biomarkers and potential treatment strategies for thrombotic events remain under investigation [ 27 , 28 , 29 , 30 ]. In 1992, Celermajer et al reported the first non-invasive endothelial function test [ 31 ].…”

“…Blood samples for MV measurements were collected in citrated tubes (sodium citrate 3.2%) and centrifuged within 30 min with a two-step centrifugation protocol (2500× g for 15 min at room temperature, followed by a second centrifugation of the supernatant at the same condition). Supernatant was collected, and platelet poor plasma was stored at −80 °C [ 29 ]. MVs detection was then performed on thawed samples using a CyFlow Cube8 ROBBY flow cytometer (Sysmex Partec GmbH, Goerlitz, Germany).…”

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“…The ACE2 enzyme then converts AngII into the metabolite Ang-(1–7), which acts as a ligand for the Mas receptor (MasR). The MAS receptor elicits signalling opposing Ang II/AT1R effects, including the inflammatory ones, and inhibiting AT1R expression [ 61 ]. Both ACE2 and MasR are present in human Leydig and Sertoli cells ( Figure 2 ).…”

“…For sHLH, it has been hypothesized that environmental factors may also trigger or exacerbate an aberrant innate and acquired immune response with massive cytokine synthesis in genetically susceptible individuals [ 144 ]. Alteration of the ACE2 enzyme activity has been indicated as an important trigger of the pathologies seen in COVID-19 patients [ 61 ]. Inactivation of the ACE2 complex leads to thrombosis in infected and noninfected tissues, aberrant sensory and neurological perception in COVID-19 patients and, most importantly, to necrosis in pulmonary, endothelial, and cardiac cells.…”

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“…The over-activation of the ENaC plays a crucial role in urinary potassium loss and subsequently reduced serum potassium levels [ 18 ]. Interestingly, ENaC and ACE2 expression share similar distributions in the tissues, including renal tubules, urinary bladder, colon epithelium, lung airway, and alveoli [ 19 , 20 ].…”