LAUSR

The COVID-19 pandemic has called enormous scientific attention to angiotensin converting enzyme 2 (ACE2) and other components of the renin-angiotensin system (RAS) since ACE2 plays a central role as the viral receptor initiating the SARS-CoV-2 cell infection process. In addition, ACE2 and other RAS components are known to play prominent roles in lung injury, which is a major cause of COVID19 morbidity and mortality. Our limited current understanding of SARS-CoV-2 and ACE2 roles, however, has made it difficult to delineate the pathophysiology associated with COVID-19. The myriad of COVID-19 symptoms, alongside the prominent role of ACE2 in SARS-CoV-2 infection, has led to conflicting recommendations regarding how ACE inhibitors (ACEi) or angiotensin receptor blockers (ARBs) that target both ACE2 and other RAS-related components should be approached in COVID-19 patient care. An early concern was that increased ACE2 resulting from ACEi or ARB treatment of hypertensive patients might increase their SARSCoV-2 infection rate. This higher SARS-CoV-2 infection rate related to increased ACE2 has been criticized, while there are suggestions that administering ACEi and ARBs might be beneficial in treating COVID-19 [1]. Upregulation of ACE2 is potentially also beneficial by maintaining Ang II conversion to the vasodilatory, anti-inflammatory and antiatherosclerotic Ang 1–7 [2], while the use of ARBs could be beneficial by blocking excessive Ang II type-1 receptor (AT1R)-mediated Ang II activation, thereby increasing Ang 1–7 levels by upregulating ACE2 activity. The potential, protective role of ACE2 in SARS-CoV-2 infection-induced COVID-19 morbidity and mortality has recently been reviewed (Supplemental Ref. [1]). In addition, not only are the effects of ACEi or ARBs potentially protective but more recently, Rho kinase (ROCK) inhibitors have also proven to be potentially useful via their ability to increase ACE2 [3]. Another line of evidence suggesting that elevated ACE2 may be of potential benefit arises from the study of renal cells as ACE2 is strongly expressed in kidney tubules. Renal impairment has been found to be the main secondary outcome of COVID-19 infection, following respiratory dysfunction (Supplemental Ref. [2]). Monteil and coworkers reported that SARS-CoV-2 directly infects human tubular kidney cells and has the ability to replicate post-infection in kidney organoids [4]. Of note, they further demonstrated that human recombinant soluble ACE2 treatment of kidney organoids significantly reduced SARS-CoV-2 infection in a dose-dependent manner [4]. These findings also argue that elevations of ACE2 are potentially beneficial. The centrality of ACE2 and therefore of the RAS to COVID-19 provides a clear rationale for the study of systems, particularly human ones, in which ACE2 and other RAS components are altered (compared to normal). One such human system is represented by patients with Gitelman’s and Bartter’s syndromes (GS/BS), two rare genetic tubulopathies. We have explored and sought to better define the human RAS and RhoA/ROCK systems ([5], Supplemental Ref. [3]) by taking advantage of their endogenously activated RAS and high Ang II levels, yet blunted Ang II-mediated cardiovascular-renal effects, normotension or hypotension. Moreover, they exhibit increased and correlated levels of both ACE2 and Ang 1–7, activation of antiinflammatory, anti-apoptotic, anti-proliferative and anti-atherosclerotic defenses, reduced oxidative stress and blunted ROCK signaling [5, 6]. In addition, these patients also have up-regulated regulator of G-protein signaling (RGS)-2. Supplementary Information The online version contains supplementary material available at https ://doi.org/10.1007/s4062 0-020-00951 -6.