key: cord-0987735-jowa3w0e authors: Silhol, François; Sarlon, Gabrielle; Deharo, Jean-Claude; Vaïsse, Bernard title: Downregulation of ACE2 induces overstimulation of the renin–angiotensin system in COVID-19: should we block the renin–angiotensin system? date: 2020-05-22 journal: Hypertens Res DOI: 10.1038/s41440-020-0476-3 sha: 10fc6127670719b8c3282f1eaee1a247abc37627 doc_id: 987735 cord_uid: jowa3w0e nan angiotensin 2 through ACE, as the decrease in ACE2 results in a lower conversion of angiotensin to angiotensin 1-7 vasodilator [12] . The lower the level of ACE2, the lesser angiotensin I [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] and angiotensin II [1] [2] [3] [4] [5] [6] [7] [8] will be degraded; thus, their plasmatic concentration gradually increases. A US intensive care unit team demonstrated that an increase in angiotensin 1-10 and a decrease in angiotensin 1-9 (its ACE2 processing product) were correlated with a poor prognosis in ARDS [1] . Thus, elevations in angiotensin II concentrations and stimulation of AT1R lead to a decrease in the stability of the pulmonary endothelium and an aggravation of respiratory distress [13, 14] . The other effects are an increased secretion of aldosterone, hypokalemia induced by kaliuresis, and increased sodium reabsorption and inflammation [15] . Hypokalemia is frequently found in patients with COVID-19. A Chinese team recently reported that hypokalemia was associated with a poor outcome (Wuhan's experience) [16] . Conversely, RAS blockers can increase ACE2 and potentially promote virus loading into the cell [17] . We believe that major imbalance in RAS induced by the downregulation of ACE2 is an essential element of unfavorable evolution in patients with COVID-19. The biological marker of this imbalance appears to be hypokalemia. Several studies in influenza and Ebola lung infections have shown the beneficial role of AT1R blockers on lung damage, with a decrease in inflammation and cytokines [18] [19] [20] [21] . In two animal studies, losartan demonstrated an increase in ACE2 expression [22, 23] . Losartan was also the molecule chosen in two trials recently started in the United States by the University of Minnesota to treat patients with COVID-19 (clinical trials. gov NCT04311177 and NCT 104312009). We began a preliminary study to document the kinetics of RAS in COVID+ patients (SAR-COV) before therapeutic evaluation (ISRA-COV). Clarification is needed to determine whether blockers of the angiotensin system have a protective or harmful effect in these patients [24] . In particular, we strongly need to evaluate how blocking the overactivation of the RAS by an AT1R blocker (such as losartan) in patients with COVID-19 could decrease respiratory decompensation and hemodynamic disorders and thus limit the number of patients with poor prognosis. Conflict of interest The authors declare that they have no conflict of interest. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Circulating angiotensin peptides levels in acute respiratory distress syndrome correlate with clinical outcomes: a pilot study Clinical features of patients infected with 2019 novel coronavirus in Wuhan World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19. World Health Organization Distribution of type-1 and type-2 angiotensin receptors in the normal human lung and in lungs from patients with chronic obstructive pulmonary disease Human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase Angiotensinconverting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis Counterregulatory actions of angiotensin-(1-7) Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Receptor recognition on by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus The discovery of ACE2 role in acute lung injury in mice Possible role of angiotensin-converting enzyme 2 and activation of angiotensin II type 2 receptor by angiotensin-(1-7) in improvement of vascular remodeling by angiotensin II type 1 receptor blockade Angiotensinconverting enzyme 2 protects from severe acute lung failure A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Induction of cardiac fibrosis by angiotensin II Hypokalemia and clinical implications in patients with coronavirus disease 2019 (COVID-19) Hypothesis: angiotensine converting enzyme inhibitor and angiotensine receptor blocker may increase the risk of severe Covid19 Antagonist of the type-1 ANG II receptor prevents against LPS-induced septic shock in rats Possible involvement of angiotensin-converting enzyme 2 and Mas activation in inhibitory effects of angiotensin II Type 1 receptor blockade on vascular remodeling LPS-stimulated cytokine production in type I cells is modulated by the renin-angiotensin system Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats Renin-Angiotensin system blockers and the COVID-19 pandemic at present there is no evidence to abandon Renin-Angiotensin system blockers