MO041: Impaired ACE2 glycosylation and protease activity lowers susceptibility to SARS-COV-2 infection in Gitelman/Bartter syndromes

Abstract BACKGROUND AND AIMS ACE2, part of the counter-regulatory arm of the renin–angiotensin system, serves both as protective toward oxidative stress and cardiovascular remodeling and as a key entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 has two isoforms, non-glycosylated and glycosylated, the latter being accountable for the binding with SARS-CoV-2. After the binding, viruses use proteases as cathepsin-L (Cat-L) to entry the cells. Both ACE2 glycosylation and Cat-L activity are pH-dependent. Gitelman and Bartter syndromes (GS/BS), rare genetic tubulopathies, are characterized by electrolytic alterations, activation of the renin–angiotensin system, yet normo-hypotension, increased levels of ACE2 and metabolic alkalosis with likely increased intracellular pH. We reported that during the first wave of COVID-19 in early 2020 none of our cohort of 128 GS/BS patients from the major hotspots in Northern Italy had been infected or suffered any major COVID-19 symptoms and in a second survey on the same cohort in 2021, we reported only eight positives, four asymptomatic and four with very light symptoms This study aims to investigate potential mechanisms as ACE2 glycosylation and Cat-L activity related to patients’ metabolic alkalosis and viral entry/infection. METHOD Mononuclear cells ACE2 glycosylation (Western blot) and blood Cat-L activity (ELISA) from 20 GS/BS patients have been compared with those from 15 healthy subjects. RESULTS Non-glycosylated ACE2 was higher in GS/BS (0.82 ± 0.19 d.u. versus 0.67 ± 0.13, P = 0.01); glycosylated ACE2 was not different (0.85 ± 0.28 in GS/BS versus 0.73 ± 0.23, P = 0.19). Cat-L activity was lower in GS/BS (3.90 ± 1.13 r.f.u. versus 5.31 ± 0.8, P