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.
Highlights
The renin–angiotensin system (RAS) is a well characterised essential hormone system with pivotal roles in vascular biology, blood pressure regulation, the nervous system, electrolyte homeostasis, tissue injury, neoplasia and lipid homeostasis [1,2]
Since its discovery two decades ago, angiotensin-converting enzyme 2 (ACE2) has been the central focus of a large number of studies that investigated the protective role of the alternate RAS in many pathological conditions including cardiovascular, renal, lung and liver disease
The fact that ACE2 breaks down potent profibrotic peptide Ang angiotensin II (II) to antifibrotic peptide Ang-(1-7) and that Ang-(1-7) administration to preclinical animal models with liver disease dramatically improves liver fibrosis provided a great opportunity to use ACE2 as a potential therapy for liver fibrosis
Summary
The renin–angiotensin system (RAS) is a well characterised essential hormone system with pivotal roles in vascular biology, blood pressure regulation, the nervous system, electrolyte homeostasis, tissue injury, neoplasia and lipid homeostasis [1,2]. The RAS has both classical and protective arms with the balance between them deciding the net effect on organ homeostasis and role in tissue injury [3]. Therapeutics that act on the RAS including the angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are commonly used in current medical practice. Additional interest in the RAS has been driven by the recognition of the essential roles of this hormone system in tissue injury including pathologies as diverse as the remodelling of cardiac tissue after myocardial infarction, the development of the vasculature in malignancy and progression of tissue fibrosis such as liver fibrosis that can result in cirrhosis [4]. It is recognised that the carboxypeptidase angiotensin-converting enzyme 2 (ACE2) determines the balance between the classical and protective RAS [4,5]
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