Renin-angiotensin system at the heart of COVID-19 pandemic

Abstract

Significant aspects of COVID-19 pandemic remain obscure. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system, whose expression dominates on lung alveolar epithelial cells, is the human cell receptor of SARS-CoV-2, the causative agent of COVID-19. We strongly encourage the concept that thorough considerations of receptor-ligand interactions should be kept at the heart of scientific debate on infection. In this idea, the whole renin-angiotensin system has to be evaluated. We hypothesize that factors related to ethnicity, environment, behaviors, associated illness, and medications involving this complex system are probably responsible for situations regarded as anomalous from both an epidemiological and a clinical point of view, but, taken together, such factors may explain most of the aspects of current outbreak. We decided to use the analogy of a play and speculate about the possible impact in this tragedy of 1) air pollution via the interference of nitrogen dioxide on ACE2 expression; 2) the dual role of nicotine; 3) the hypothetical involvement of ACE2 polymorphisms, the relationships of which with ethnic factors and susceptibility to cardiovascular disease seems intriguing; 4) the impact on the severity of infection of hypertension and related medications acting on the renin/angiotensin system, and, finally, 5) the possible helpful role of chloroquine, thanks to its capacity of modifying ACE2 affinity to the viral spike protein by altering glycosylation. This hypothesis paper is an urgent call for the development of research programs that aim at questioning whether the putative protagonists of this tragedy are real-life actors in COVID-19.

Keywords: ACE2; COVID-19; Mechanisms.

Fig. 1

The stage. Scene 1: In the renin angiotensin system, angiotensin-converting enzyme (ACE) cleaves angiotensin I (Ang I) to produce angiotensin II (Ang II). Ang II action is mediated by the angiotensin II receptor type 1 (AT1R). ACE, Ang II, and AT1R appears to promote lung injury. Angiotensin converting enzyme 2 (ACE2) removes a single residue from Ang II to generate the vasodilator Ang-(1–7), counterbalancing the effects of Ang II. The main actions described for Ang-(1–7) are associated with Mas receptor activation. The ACE2/Ang-(1–7)/Mas arm high activation is effective in reducing lung inflammation, fibrosis, and pulmonary artery hypertension. Scene 2: SARS-CoV-2 uses ACE2 as a receptor for entry into the cell, once the S protein has been primed by a serine protease. Scene 3: The expression of ACE2 and the balance of ANG II/ANG 1–7 influence the course of the disease. Accordingly, ACE 2 may be upregulated due to the individual polymorphism, NO2 associated with air pollution, and ACE inhibitors/Sartans. ACE2 affinity for spike protein may be lowered by hydroxy-chloroquine. Sartans may inhibit the deleterious effects of Ang II during the late phase of the infection. Footnote: Nicotine may have dual action by enhancing ACE and down-regulating ACE2.