ROLE OF ACE2 GLYCOSYLATION AND RHO KINASE INHIBITION IN THE INFECTIOUS/THERAPEUTIC PROCESS OF COVID-19. INSIGHTS FROM GITELMAN'S AND BARTTER'S SYNDROMES PATIENTS

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Objective: ACE2 in addition to be the counterregulatory enzyme in RAS system, is the entry point of SARS-CoV-2. Several studies have reported its protective role in SARS-CoV-2-induced Acute Distress Syndrome (ARDS) and a relationship between Rho kinase (ROCK), ARDS and increased ACE2 levels induced by ROCK inhibitors. Cells’ ACE2 expression is in two different immunoreactive forms, glycosylated and unglycosylated, but only the glycosylated is associated with viral binding. ACE2-glycosylation is driven by the acidic pH of intracellular endosomes/lysosomes/Golgi vesicles and this represents the rational to the prophylactic/therapeutic use of antimalarial drugs as hydroxychloroquine/chloroquine, weak bases that increase the pH of vesicles, which leads to the production of unglycosylated ACE2 and therefore reduction/inhibition of viral binding. Gitelman's and Bartter's syndrome patients (GS/BS) (rare genetic tubulopathies) have activated RAS, high Ang II yet normotension/hypotension, metabolic alkalosis, increased and related ACE2 and its product Ang 1–7 levels, reduced ROCK activity therefore may provide information on the protective role of increased ACE2 levels and ROCK inhibition. This study has assessesed the impact of COVID-19 on GS/BS Design and method: We performed a telephone survey on more than 100 GS/BS from the hotspots of COVID-19 pandemic in Northern Italy (Veneto, Lombardia, Emilia Romagna). COVID-19 prevalence in the general population was obtained from Civil Protection's official data and the estimated prevalence from published data. 95% CI values processed with Clopper-Pearson method using R-software Results: None of GS/BS reported infection/symptoms of COVID-19, which was statistically not significant vs the prevalence of COVID-19 in the general population in the Italian hotspots due to the low prevalence of GS/ BS (rare diseases) (95% CI 0.0 -3.0% vs 0.65%, 95% CI 0.6–0.7%). It becomes significant vs the estimated prevalence in the general population in the hotspot regions (8.7%, 95% CI 8.7–8.8%, (C2), p = 0.004) Conclusions: GS/BS might serve as a human model of increased ACE2 for ex-vivo mechanistic investigation on viral binding; provide additional evidence on the absence of high ACE2 levels-increased risk of COVID-19; demonstrate that suspension of treatments with ACE inhibitors/ARBs, which increase ACE2 expression, to reduce the risk of infection is not rationale.