An Overview of Angiotensin-converting Enzyme 2 (ACE2)

An outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started in Wuhan, China, at the end of 2019 has become a global pandemic. Both SARS-CoV-2 and SARS-CoV enter host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various human organs. ACE2 catalyzes angiotensin II conversion to angiotensin-(1-7), and the ACE2/angiotensin-(1-7)/MAS axis counteracts the negative effects of the renin-angiotensin system (RAS), which plays important roles in maintaining the physiological and pathophysiological balance of the body. In addition to the direct viral effects and inflammatory and immune factors associated with COVID-19 pathogenesis, ACE2 downregulation and the imbalance between the RAS and ACE2/angiotensin-(1-7)/MAS after infection may also contribute to multiple organ injury in COVID-19.

ACE2 mediates SARS-CoV-2 infection

Entry into host cells is the first step of viral infection. A spike glycoprotein on the viral envelope of the coronavirus can bind to specific receptors on the membrane of host cells. Previous studies have shown that ACE2 is a specific functional receptor for SARS-CoV. Further studies showed that the binding affinity of the SARS-CoV-2 spike glycoprotein to ACE2 is 10- to 20-fold higher than that of SARS-CoV to ACE2. SARS-CoV-2 enters the lungs, where the spike glycoprotein of the virus binds to ACE2 on cells, allowing the virus enter the cells. Some transmembrane proteinases, such as transmembrane protease serine 2 (TMPRSS2) and a disintegrin metallopeptidase domain 17 (ADAM17) also participate in this process. For example, SARS-CoV-2 can use TMPRSS2 for spike protein priming in cell lines. The infected cells and inflammatory cells stimulated by viral antigens can produce pro-inflammatory cytokines (PICs) and chemokines to activate immunological reactions and inflammatory responses to combat the viruses. Cell-free and macrophage-phagocytosed viruses in the blood can be transmitted to other organs and infect ACE2-expressing cells at local sites.

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Fig1. A model for the process of SARS-CoV-2 entering host cells in the lungs and attacking other organs. (Crit Care, 2020)

SARS-CoV infection can cause injury to multiple organs, such as the heart, kidney, liver, skeletal muscle, central nervous system, and adrenal and thyroid glands, besides the lungs. Most critically ill patients with COVID-19 also had multiple organ damage, including acute lung injury, acute kidney injury, cardiac injury, liver dysfunction, and pneumothorax.

Acute lung injury. Similar to the pathological features of SARS and MERS, severe diffuse alveolar damage, such as extensive edema, hyaline membrane formation, inflammatory infiltrates, microthrombi formation, organization, and fibrosis, was also observed in COVID-19, but with more cellular fibromyxoid exudates in the alveoli and small airways. The findings suggest that the RAS and ACE2 downregulation contribute to the pathogenesis of lung injury in COVID-19.

Acute cardiac injury. The beneficial role of the ACE2/angiotensin-(1-7)/MAS axis in the heart has been well demonstrated. The significant downregulation of ACE2 and upregulation of Ang-II in COVID-19 results in RAS over-activation, and loss of the protective effects of angiotensin-(1-7) may aggravate and perpetuate cardiac injuries.

Digestive system injury. The findings indicate that most acute hepatic injury may not be due to virus infection, but is highly likely due to other causes, such as drug hepatotoxicity, hypoxia, and systemic inflammation. Whether SARS-CoV-2 causes damage to the bile ducts by binding with ACE2 on cholangiocytes requires further investigation.

Acute kidney injury. ACE2 is highly expressed in the kidney, especially in the apical membranes of proximal tubular epithelial cells, suggesting that the kidney is another target of SARS-CoV-2. Moreover, an imbalance between Ang-II and angiotensin-(1-7) caused by ACE2 deficiency may aggravate the vulnerability of the kidney to other factors causing acute kidney injury (AKI).

Other organ and tissue injuries. Clinical presentation of acute pancreatitis has been reported in patients with COVID-19. ACE2/angiotensin-(1-7) plays a protective role in diabetes by improving pancreatic β cell survival, stimulating insulin secretion, and reducing insulin resistance. The ACE2/angiotensin-(1-7)/MAS axis exerts protective effects against muscle atrophy. SARS-CoV-2 was detected in the cerebrospinal fluid of a patient with encephalitis. Considering that SARS-CoV-2 has a much higher affinity for its receptor (ACE2) than SARS-CoV, the former could be capable of infecting and damaging the central nervous system. ACE2 is also expressed in the endothelial cells of small and large blood vessels, and the vascular endothelium can produce angiotensin-(1-7). The ACE2/angiotensin-(1-7)/MAS axis induces vasodilatory, antiproliferative, and antithrombotic effects in the vasculature.

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