Downregulation of ACE2 induces overstimulation of the renin–angiotensin system in COVID-19: should we block the renin–angiotensin system?

Abstract

Severe acute respiratory syndrome coronavirus 2 is the cause of the ongoing coronavirus disease-19 (COVID-19) pandemic. Mortality is mainly due to acute respiratory distress syndrome (ARDS) [1]. High blood pressure appeared to be an independent factor for severity in patients with COVID-19 [2, 3]. The renin-angiotensin system (RAS) is a hemodynamic and biological system that regulates blood pressure, plasma potassium, and the stability of pulmonary epithelial membranes (Fig. 1) [4]. In this system, two antagonistic pathways are balanced. The first is the angiotensinogen pathway that transforms angiotensinogen into angiotensin I (by renin), and then converts it into angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II attaches to angiotensin II type 1 receptor (AT1R) and activates the system to induce vasoconstriction, aldosterone secretion stimulation, hypokalemia, and pulmonary epithelium degradation [5]. The second way in which the angiotensin system is balanced involves a second angiotensin converting enzyme (ACE2) [6, 7]. This pathway transforms a part of angiotensin I [1-10] and angiotensin II [1-8] before it attaches to its AT1R receptor. The angiotensin I and II phosphorylation products are angiotensin 1-9 and angiotensin 1-7. They attach to the angiotensin II type 2 receptor receiver, inducing antagonist effects compared with AT1R [8]. In the infection phase (Fig. 2), COVID-19 virus uses the enzymatic receptor of ACE2 to penetrate the host cell [9, 10]. Coronavirus binding with ACE2 has been shown to lead to a downregulation of ACE2 [11], contributing to an increase in

Intracranial hemorrhage in coronavirus disease 2019 (COVID-19) patients

“…This hypothesis is further supported by recent electron microscopic studies that have demonstrated the presence of viral inclusion particles within the endothelium, and viral RNA detection in cerebrospinal fluid [ 41 , 42 ]. Second, entry of the SARS-CoV-2 virus into cells results in marked reduction in ACE-2 levels [ 43 ]. Since this protein usually catalyzes conversion of angiotensin II to counter-regulatory angiotensin 1-7 [ 44 , 45 ], reduction in its levels results in enhanced and unopposed effects angiotensin II via the ACE-angiotensin II-AT1 receptor axis [ 43 – 45 ].…”

Systems Biology Approaches for Therapeutics Development Against COVID-19

“…Apart from lungs, ACE2 was also expressed in the extrapulmonary surface. SARS-CoV-2 enters the cell by membrane diffusion and slows down the regulation of ACE2 receptor (Qian et al, 2013;Silhol et al, 2020). TMPRSS2 based entry of SARS-CoV-2 has been observed when cleavage of the S1/S2 site is mediated by furin in the virus-infected cell (Coutard et al, 2020).…”

Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection

“…Patients with existing cardiovascular diseases face a higher risk of COVID-19 (Kuno et al, 2020;Li et al, 2020b;Richardson et al, 2020b). In patients with cardiovascular diseases, diabetes mellitus, and hypertension treated with ACE inhibitors and ARBs, the expression of ACE2 contributes to worsening the prognosis of COVID-19 patients (Birnbaum, 2020;Cannata et al, 2020;Fosbøl et al, 2020;Mackey et al, 2020;Pirola and Sookoian, 2020;Silhol et al, 2020). In contrast, several recent clinical studies provide evidence that ACE inhibitors and ARBs may be beneficial in COVID-19 patients with hypertension and, hence, recommend continuing ACE inhibitors and ARBs (Kang et al, 2020;Mackey et al, 2020).…”