key: cord-0979743-1lkzcslx
authors: Álvarez-Aragón, Luis Miguel; Cuesta-Muñoz, Antonio Luis; Álvarez-López, Inmaculada
title: Inquiring into Benefits of Independent Activation of Non-Classical Renin-Angiotensin System in the Clinical Prognosis and Reduction of COVID-19 mortality
date: 2020-04-08
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa402
sha: abd088a08df4e14e71bbca3186bb9b414a3e589d
doc_id: 979743
cord_uid: 1lkzcslx

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A c c e p t e d M a n u s c r i p t

We have read with great interest the elegant manuscript by Hanff et al [1] proposing a very interesting association between the classical renin-angiotensin system (RAS) and angiotensinconverting enzyme 2 (ACE2) dysregulation present in cardiovascular disease (CVD) and the high mortality index in patients with CVD and coronavirus disease 2019 (COVID-19). The authors state that pharmacological inhibition of classical RAS could have two simultaneous and incompatible outcomes. On the one hand, it will decrease the proinflammatory effect of Angiotensin II with its subsequent benefit on decreasing the risk of acute respiratory distress syndrome (ARDS) observed in these patients, and on the other hand, it will increase ACE2 expression and therefore the virulence of SARS-Cov2.

It has been shown that coronaviruses, in order to access the inside of their host cells, first must bind to a host receptor to be able to fuse both viral and host membranes [2] . In humans, the host receptor is ACE2 and, like SARS coronavirus (SARS-CoV), SARS-CoV-2 also needs ACE2 to attack human alveolar epithelial cells [3] . Therefore, this also makes ACE2 crucial in the infectivity and pathogenesis of SARS-CoV-2.

In addition to the heart and kidneys, the classical RAS and ACE2 are also present in the lungs [4] . It is pertinent to evoke that ACE2 is also a fundamental component in the ACE2-Angiotensin(1-7)-MasR axis, also known as non-classical RAS, indicating, therefore, the existence of non-classical RAS also in the lungs. Non-classical RAS is a counter-regulatory system of the classical RAS in that its end product, Angiotensin(1-7), which after binding to the Mas receptor, presents important antiinflammatory, anti-proliferative, anti-fibrotic, natriuretic and vasodilator effects [5] , actions completely opposed to those promoted by the end product of the classical RAS Angiotensin II.

While pharmacological exclusion or initiation of classical RAS inhibition as an adjuvant treatment for SARS-Cov2 in patients with CVD is elucidated, and considering that COVID-19 patients present downregulation of ACE2 [1] , and hence low Angiotensin(1-7), the direct pharmacological activation of the non-classical RAS would be an attractive and plausible approach to tackle the reduction of Angiotensin(1-7) to lessen the unwanted effects of Angiotensin II.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a group of oral medications used to treat type 2 diabetes, however, large epidemiological studies have demonstrated that SLGT2 inhibitors present strong nephro-and cardiovascular-protective effects. In addition, in vitro studies in human renal cells treated with SLGT2 inhibitors have shown an increment in Angiotensin(1-7) due to the independent activation of the non-classical RES, leading to important anti-inflammatory and anti-M a n u s c r i p t fibrotic effects [6, 7] . By analogy, it is reasonable to assume that SLGT2 inhibitors could also activate the non-classical RES in the lungs.

A vast majority of diabetic patients also present CVD and many of them are treated with SLGT2 inhibitors to both lower blood glucose and protect the kidney and heart. Hence, would diabetic patients with CVD and treated with SLGT2 inhibitors present a milder ARDS as compared to those with a different treatment? Would they have a better clinical prognosis? And, would the use of SLGT2 inhibitors in non-diabetic patients improve clinical prognosis as well? These are interesting questions since the answers might open a new door to counteract the devastating consequences of the proinflammatory cytokine storm present in COVID-19 patients.

We declare no conflict of interest.

Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System-a Call for Epidemiologic Investigations

Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decadelong structural studies of SARS coronavirus

Structure analysis of the receptor binding of 2019-nCoV

Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation

Counterregulatory renin-angiotensin system in cardiovascular disease

Mechanical forces in diabetic kidney disease: a trigger for impaired glucose metabolism

Beat it early: putative renoprotective haemodynamic effects of oral hypoglycaemic agents

A c c e p t e d M a n u s c r i p t