key: cord-0766130-gegz7dpv
authors: Davis, Paul A.; Bertoldi, Giovanni; Calò, Lorenzo A.
title: On the imbalanced protective arm of RAS in COVID‐19: Lesson from rare genetic tubulopathies
date: 2021-04-21
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14075
sha: fc2b8876e042758b2202bdb3662a08b8cd62ec09
doc_id: 766130
cord_uid: gegz7dpv

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The critical role of the renin-angiotensin system (RAS) in has been recently reviewed 1 and, as in other reports since the beginning of the COVID-19 pandemic, it is suggested that SARS-CoV-2, which has ACE2 as a primary target for initiating the cell infection process, compromises the ACE2 production of angiotensin-(1-7) and angiotensin-(1-9) leading to decreased Mas and Angiotensin II (Ang II) AT2-receptors (AT2Rs) stimulation. In addition, SARS-CoV-2 effects on ACE2 lead to overstimulation of Ang II AT1-receptors (AT1Rs) by less degradation of Ang II. 1 Thus, the pathology of COVID-19, eg, excessive immune response, endothelial dysfunction, increased clotting, thromboses, and stroke may be linked to an imbalance of the two arms of the renin-angiotensin system (RAS), where the ACE2 counterregulatory linked arm has numerous beneficial actions including anti-inflammatory, anticoagulative, anti-fibrotic 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 SARS-CoV-2 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 COVID-19.

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 II-mediated cardiovascular-renal 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 pathways 3, 4 and may also explain their elevated anti-inflammatory, antiapoptotic, antiproliferative, and antiatherosclerotic defences, decreased oxidative stress and Rho kinase signalling. [3] [4] [5] 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 1-7, 3,6 which also fits with GS/BS having an endogenous antagonism of Ang II signalling via AT1Rs. [3] [4] [5] [6] Given their endogenously higher ACE2 levels, GS/BS patients might be expected to differ in their response to SARS-CoV-2 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 COVID-19 hot spots (Lombardia, Veneto, and Emilia Romagna) asking them if they had any COVID-19 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 COVID-19 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 SARS-CoV-2 infection. However, accepting that we may have missed SARS-CoV-2 infections in our

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