ACE2 and prognosis of COVID‐19: Insights from Bartter's and Gitelman's syndromes patients

To the Editor,

The relationship between renin‐angiotensin system (RAS) and coronavirus disease 2019 (COVID‐19) pandemic and, in particular, RAS as part of the coronavirus 2 (CoV‐2) infection process via angiotensin‐converting enzyme 2 (ACE2), the entry point of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has resulted in conflicting suggestions regarding how RAS and its role(s) should inform treating COVID‐19. ACE inhibitors or angiotensin II (Ang)‐type 1 receptor blockers (ARBs), in fact, have been suggested to be avoided as they potentially upregulate ACE2 ¹ and, conversely, there are suggestions that ARBs might be beneficial ² as SARS‐CoV‐2 causing ACE2 downregulation slows the Ang II conversion to the vasodilatory, anti‐inflammatory, antioxidant and antiatherosclerotic Ang 1‐7, ³ , ⁴ , ⁵ and the use of ARBs by blocking the excessive Ang II type‐1 receptors activation, would be beneficial upregulating ACE2 activity and increasing Ang 1 to 7 levels.

We have read with great interest the very recently published article by Cheng and coworkers, ⁶ who reviewed the correlation between severe risk factors for COVID‐19 and ACE2. Their review highlighted the potential protective role of ACE2 in SARS‐CoV‐2 infection‐induced acute respiratory distress syndrome, the major cause of COVID‐19 mortality as well as other risk factors such as hypertension, diabetes, and cardiovascular disease that are linked to COVID‐19 morbidity and mortality.

We feel that our studies in Bartter's and Gitelman's syndrome patients (rare genetic tubulopathies) to explore and better define the human RAS system ⁷ provide further insight on the protective effects of ACE2 in humans including the effects on prognosis of COVID‐19. Specifically, these patients have an activated RAS and high Ang II levels, yet blunted Ang II‐mediated cardiovascular effects and normotension or hypotension, activation of antiatherosclerotic and anti‐inflammatory defenses, reduced oxidative stress ⁷ and, directly relevant to the discussion regarding ACE2, they have increased and correlated levels of both ACE2 and Ang 1‐7, ⁸ therefore, a prevalence of the counterregulatory ACE2‐Ang 1‐7‐MasR axis over the classical ACE‐Ang II‐AT1R regulatory axis of RAS. ⁹ These data suggest that increasing ACE2 via ARBs and ACE inhibitors might be beneficial via effects on Ang 1‐7 for patients infected by SARS‐CoV‐2 as this has been shown for ACE2 in hyperoxic lung injury. ¹⁰

Moreover, our cohort of Gitelman's and Bartter's patients provides evidence, admittedly anecdotal, and circumstantial, allaying the concerns raised that increased ACE2 might provide more targets for the CoV‐2 virus. A telephone survey of over 100 of our Gitelman's and Bartter's patients, all from the Northern Italy Regions Veneto, Lombardia and Emilia Romagna, the hotspots of the COVID‐19 pandemic in Italy, found none of them infected with COVID‐19, making increased risk to COVID‐19 due to increased ACE2 unlikely. ¹¹

Finally, the increased and correlated levels of both ACE2 and Ang 1‐7 noted in Gitelman's and Bartter's patients also add support to Cheng and coworkers, ⁶ suggestion that drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID‐19 in the future.