ACE2: from protection of liver disease to propagation of COVID-19

Abstract

Twenty years ago, the discovery of angiotensin-converting enzyme 2 (ACE2) was an important breakthrough dramatically enhancing our understanding of the renin–angiotensin system (RAS). The classical RAS is driven by its key enzyme ACE and is pivotal in the regulation of blood pressure and fluid homeostasis. More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans.

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“…A previous study also indicated that underlying diseases such as hypertension (OR = 2.72, 95% CI: 1.60, 4.64) and diabetes (OR = 3.68, 95% CI: 2.68, 5.03) are risk factors for critical disease/mortality ( 56 ). Early publications reported a “harmful hypothesis” that SARS-CoV-2 binds to target cells via angiotensin-converting enzyme 2 (ACE2), and patients with hypertension usually have increased expression of ACE2 due to the use of renin angiotensin system inhibitors ( 57 ). Although some studies indicated that ACE inhibitors (angiotensin converting enzyme inhibitors) and ARB (angiotensin-receptor blockers) therapy was harmful in COVID-19 patients, an updated meta-analysis concluded that ACEI/ARB therapy does not contribute to increased risk of mortality or severe manifestations among COVID-19 patients ( 58 , 59 ).…”

Extracellular Matrix Remodeling in Chronic Liver Disease

“…It is well-known that Ang II is the central effector that stimulates HSCs to produce pro-fibrotic cytokines, such as TGF-β1 and CTGF, which further increases hepatic resistance to portal flow and enhanced matrix formation [ 138 •, 142 ••, 143 – 145 ]. However, ACE2 is also the major cellular entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) as a cellular receptor to infect alveolar epithelial cells, causing the severe respiratory disease Coronavirus disease 2019 (COVID-19) in humans [ 146 , 147 ].…”

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“…Furthermore, fermented milk, another natural ACE inhibitor, is widely consumed in Bulgaria, Greece and Turkey, all of which also have had relatively low mortality rates. These findings may be mechanistically explained by a reduced production of angiotensin II (Ang II), which can act as a proinflammatory molecule, contributing to acute lung injury and favoring more severe COVID-19 manifestations ( 71 , 72 ). In addition, the microbiota present in fermented dairy products is linked to the induction of gut-mediated pulmonary immunity, providing protection against respiratory infections and inflammation ( 73 – 75 ).…”

“…Within the renin-angiotensin system (RAS), ACE produces pro-inflammatory Ang II, which is in turn cleaved by ACE2, resulting in the formation of anti-inflammatory Ang1-7. Given this association, ACE activity can be considered proinflammatory, whereas ACE2 exerts anti-inflammatory effects by opposing ACE ( 71 , 72 ). A functional insertion/deletion (I/D) polymorphism (rs1799752) in intron 16 of the ACE gene is the most studied RAS-associated polymorphic variant and ( 118 ) has been investigated among patients with SMI ( 119 – 128 ).…”