ACE2 and SARS-CoV-2 Infection Risk: Insights From Patients With Two Rare Genetic Tubulopathies, Gitelman's and Bartter's Syndromes

Abstract

COVID-19 is spreading globally with the angiotensin converting enzyme (ACE)-2 serving as the entry point of SARS-CoV-2 virus. This raised concerns how ACE2 and the Renin-Angiotensin (Ang)-System (RAS) are to be dealt with given their roles in hypertension and their involvement in COVID-19's morbidity and mortality. Specifically, increased ACE2 expression in response to treatment with ACE inhibitors (ACEi) and Ang II receptor blockers (ARBs) might theoretically increase COVID-19 risk by increasing SARS-CoV-2 binding sites. However, ACE2 is part of the protective counter-regulatory ACE2-Ang1-7-MasR axis, which opposes the classical ACE-AngII-AT1R regulatory axis. We used Gitelman's and Bartter's syndromes (GS/BS) patients, rare genetic tubulopathies that have endogenously increased levels of ACE2, to explore these issues. Specifically, 128 genetically confirmed GS/BS patients, living in Lombardia, Emilia Romagna and Veneto, the Northern Italy hot spots for COVID-19, were surveyed via telephone survey regarding COVID-19. The survey found no COVID-19 infection and absence of COVID-19 symptoms in any patient. Comparison analysis with the prevalence of COVID-19 in those regions showed statistical significance (p < 0.01). The results of the study strongly suggest that increased ACE2 does not increase risk of COVID-19 and that ACEi and ARBs by blocking excessive AT1R-mediated Ang II activation might favor the increase of ACE2-derived Ang 1-7. GS/BS patients' increased ACE2 and Ang 1-7 levels and their characteristic chronic metabolic alkalosis suggest a mechanism similar to that of chloroquine/hydroxychloroquine effect on ACE2 glycosylation alteration with resulting SARS-COV-2 binding inhibition and blockage/inhibition of viral entry. Studies from our laboratory are ongoing to explore GS/BS ACE2 glycosylation and other potential beneficial effects of BS/GS. Importantly, the absence of frank COVID-19 or of COVID-19 symptoms in the BS/GS patients cohort, given no direct ascertainment of COVID-19 status, suggest that elevated ACE2 levels as found in GS/BS patients at a minimum render COVID-19 infection asymptomatic and thus that COVID-19 symptoms are driven by ACE2 levels.

Age and genotype dependent erythropoietin protection in COVID-19

“…ACE I/D polymorphism genetic testing could be predictive and guide patient triage and treatment decision making as individuals with the DD genotype are predisposed to a more severe COVID-19 disease course[ 59 ]. Research evidence supports the notion that endogenously[ 109 , 112 ] and exogenously increased EPO levels[ 123 ] could break the vicious circle of persistent ACE D allele augmented Ang II stimulation on PAI-1, IL-6 and FGF23 by both synergistic and individual inhibition[ 21 , 122 , 123 , 127 , 134 ]. Whenever the administration of rhEPO is not possible due to contraindications or heightened prothrombotic risk, EPO derivatives can coax EPO’s tissue-protective activity via its TPR for therapeutic use without the risks attributed to EPO’s hematological actions[ 10 , 14 , 134 ].…”

“…Second, RAS influence on EPO levels likely represents an amalgam of complex, intercalated and interrelated set of signals involving multiple molecular mechanisms[ 12 , 32 , 103 - 106 ]. Endogenously elevated EPO levels due to hypoxia in high altitude[ 107 , 108 ] or in human genetic models seem protective[ 109 ] while low EPO levels are associated with dismal COVID-19 prognosis (Figure 1 )[ 41 ]. Epidemiological studies suggest that physiological adaptation in a hypoxic environment at high altitude may protect persons from the severe impact of acute infection caused by SARS-CoV-2[ 107 , 108 ].…”

“…Furthermore, studies in patients with inherited genetic defects in specific kidney transporters and ion channels such as Gitelman’s and Bartter’s Syndromes (GS/BS) showed a statistically significant absence of COVID-19 infection and COVID-19 symptoms (Figure 1 )[ 109 ]. In GS/BS patients, the above-mentioned genetic defects result in defective salt reabsorption in the thick ascending limb of loop of Henle[ 109 ].…”

“…Furthermore, studies in patients with inherited genetic defects in specific kidney transporters and ion channels such as Gitelman’s and Bartter’s Syndromes (GS/BS) showed a statistically significant absence of COVID-19 infection and COVID-19 symptoms (Figure 1 )[ 109 ]. In GS/BS patients, the above-mentioned genetic defects result in defective salt reabsorption in the thick ascending limb of loop of Henle[ 109 ]. The resulting salt wasting, hypokalemia, and metabolic alkalosis with relatively low levels of serum chloride induce chronic RAS activation with elevated Ang II levels but due to AT1R signaling defects a hypertensive phenotype is not seen[ 111 ].…”

“…The resulting salt wasting, hypokalemia, and metabolic alkalosis with relatively low levels of serum chloride induce chronic RAS activation with elevated Ang II levels but due to AT1R signaling defects a hypertensive phenotype is not seen[ 111 ]. Instead, endogenously increased levels of aberrantly glycosylated ACE2[ 112 ] and Ang 1-7 counteract Ang II effects[ 109 , 112 ]. Intriguingly, GS/BS patients also demonstrate Ang II receptor type 2 dependent increase in EPO levels[ 103 ] and lack of Ang II induced increase of the PAI-1 gene and protein expression compared to healthy adults[ 113 ], both phenomena being possibly protective against COVID-19 at any age.…”