On the imbalanced protective arm of RAS in COVID‐19: Lesson from rare genetic tubulopathies

Abstract

The critical role of the reninangiotensin system (RAS) in COVID19 has been recently reviewed1 and, as in other reports since the beginning of the COVID19 pandemic, it is suggested that SARSCoV2, which has ACE2 as a primary target for initiating the cell infection process, compromises the ACE2 production of angiotensin(17) and angiotensin(19) leading to decreased Mas and Angiotensin II (Ang II) AT2receptors (AT2Rs) stimulation. In addition, SARSCoV2 effects on ACE2 lead to overstimulation of Ang II AT1receptors (AT1Rs) by less degradation of Ang II.1 Thus, the pathology of COVID19, eg, excessive immune response, endothelial dysfunction, increased clotting, thromboses, and stroke may be linked to an imbalance of the two arms of the reninangiotensin system (RAS), where the ACE2 counterregulatory linked arm has numerous beneficial actions including antiinflammatory, anticoagulative, antifibrotic effects along with endothelial, and neural protection that opposes the deleterious effects caused by heightened stimulation of the Ang II AT1Rs RAS regulatory arm.2 Of note, preclinical studies with AT2Rs agonists suggest that AT2Rs stimulation may be a therapeutically effective treatment of the various organ disorders in the lung, vasculature, or brain caused by SARSCoV2 infection.1 We would like to point out results from several decades’ of our research on Gitelman s and Bartter s syndromes (GS/BS) patients that provide in vivo human data that directly address the role of RAS system balance and suggest that increased ACE2 has beneficial effects with respect to COVID19. GS/BS patients are rare genetic tubulopathies and are characterised by hypokalemia, metabolic alkalosis, endogenously activated RAS, and high Ang II levels; yet, they usually present normotension or hypotension, along with blunted Ang IImediated cardiovascularrenal effects.3 Moreover, they have the activation of Ang II signalling via AT2Rs,3,4 which likely represents a major factor in the mechanism(s) that produces the blunted Ang II signalling via AT1R and related pathways3,4 and may also explain their elevated antiinflammatory, antiapoptotic, antiproliferative, and antiatherosclerotic defences, decreased oxidative stress and Rho kinase signalling.35 Note that this list of effects present in GS/BS patients mirrors those suggested as enhancing protective RAS via Ang II AT2Rs agonists.1 Of particular interest is that GS/BS patients have increased levels of ACE2 that correlate with their increased Ang 17,3,6 which also fits with GS/BS having an endogenous antagonism of Ang II signalling via AT1Rs.36 Given their endogenously higher ACE2 levels, GS/BS patients might be expected to differ in their response to SARSCoV2 exposure and/or infection. With this in mind, we have recently performed a telephone survey on more than 100 of our GS/BS patients’ cohort living in Italian COVID19 hot spots (Lombardia, Veneto, and Emilia Romagna) asking them if they had any COVID19 symptoms (fever, cough, sore throat, asthenia, dyspnea, myalgia, anosmia/hyposmia, or ageusia). We found none, data that were statistically significant when analysed using those Regions COVID19 prevalence as estimated by Signorelli et al at the time of the survey (April 2020).7 The interpretation of our results is limited by the small cohort, in line with the rare nature of their syndromes, and that all of our GS/BS patients had not been tested for SARSCoV2 infection. However, accepting that we may have missed SARSCoV2 infections in our cohort, our findings are consistent with their ACE2 levels rendering BS/GS either asymptomatic, ie, resistant to COVID19 or in fact resistant to SARSCoV2 infection, both of which interpretations point to ACE2 levels as key to SARSCoV2/COVID19. (Manuscript submitted). Another feature of GS/BS patients that may affect ACE2 is their metabolic alkalosis.3 This alkalosis may relate to the effects of Chloroquine (CQ) and hydroxychloroquine (HCQ) affecting ACE2.8,9 Central to CQ and HCQ effects are that they alkalize the transGolgi Network/postGolgi pathway which then compromises ACE2’s glycosylation. This effect, while not affecting ACE2 membrane expression, significantly reduced viral binding/infectivity of SARSCoV.8 We suggest that the GS/BS patients’ metabolic alkalosis might increase the endosome pH, mimicking CQ’s and HCQ effect, and thereby bring about aberrant ACE2 glycosylation resulting in an environment hostile also to SARSCoV2 infection or COVID19 symptoms.9 Of note, both patients treated with CQ and HCQ and GS/BS patients can exhibit a prolonged QT interval, which further suggests that both likely affect similar systems.3,10,11 Whether there is altered ACE2 glycosylation in addition to increased ACE2 found in GS/BS patients is the subject of an ongoing study in our laboratory.