The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research

Prestes, Thiago Ruiz Rodrigues; Rocha, Natália Pessoa; Miranda, Aline Silva de; Teixeira, Antônio Lúcio; Simões‐e‐Silva, Ana Cristina

doi:10.2174/1389450117666160727142401

Cited by 274 publications

(225 citation statements)

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“…Genetic ACE2 deficiency is associated with upregulation of inflammatory mediators, elevated inflammatory responsiveness to proinflammatory stimuli, and enhanced Ang II-induced cardiac and aortic remodeling [36,37]. The anti-inflammatory effects of ACE2 are exerted mostly through the ACE2-Ang-(1-7) axis against Ang II-AT 1 activities [38].…”

Section: Functions Of Ace2mentioning

confidence: 99%

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

Xiao

Sakagami

Miwa

2020

Viruses

176

177

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Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.Viruses 2020, 12, 491 2 of 10 Profile of ACE2Human angiotensin-converting enzyme-related carboxypeptidase ACE2 is encoded by the ACE2 gene which maps to chromosome Xp22 [6]. ACE2 is a type I transmembrane protein, comprised of an extracellular heavily N-glycosylated N-terminal domain containing the carboxypeptidase site and a short intracellular C-terminal cytoplasmic tail [7]. The N-terminal peptidase domain is also the SARS-CoV binding site [8]. There are two forms of ACE2 protein: cellular (membrane-bound) form and circulating (soluble) form. Cellular ACE2 protein is the full-length protein which is expressed abundantly in pneumocytes and enterocytes of the small intestine [9]. ACE2 is also expressed in vascular endothelial cells of the heart, the kidneys, and other organs, such as the brain. However, ACE2 is absent in the spleen, thymus, lymph nodes, bone marrow, and cells of the immune system (including B and T lymphocytes, and macrophages) [10,11].Circulating ACE2 (with the N-terminal peptidase domain) is cleaved from the full-length ACE2 on the cell membrane by the metalloprotease ADAM17 and then released into the extracellular environment [7]. The type II transmembrane serine protease, TMPRSS2 was found to compete with ADAM17 for ACE2 shedding but cleaves ACE2 differently. Both ADAM17 and TMPRSS2 remove a short C-terminal fragment from ACE2. Arginine and lysine residues within amino acids 652 to 659 are critical for ADAM17 shedding, whereas arginine and lysine residues within amino acids 697 to 716 are essential for TMPRSS2 shedding. Only cleavage by TMPRSS2 results in augmented SARS-CoV cell entry [12][13][14][15]. There are two ways for SARS-CoV to enter the target cell: endocytosis, and fusion of the viral membrane with a membrane of the target cell, which is 100 times more efficient than endocytosis for viral replication [16]. With the help of TMPRSS2, ADAM17-regulated ectodomain shedding of ACE2 could induce SARS-CoV cell entry through endocytosis [7,12]; however, ADAM17 activity is not required for SARS-CoV cell entry through fusion [12]. As the N-terminal domain is the coronavirus binding site, circulating ACE2 also binds to the virus. Iwata-Yoshikawa et al. infected both ...

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Section: Functions Of Ace2mentioning

confidence: 99%

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

Xiao

Sakagami

Miwa

2020

Viruses

176

177

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“…The RAS system is associated with inflammation via angiotensin II, and ACE2 alters RAS activity from proinflammatory to anti-inflammatory responses. 7 Specific inhibitors such as angiotensin II type 1 receptor (AT1R) antagonist, losartan, have been shown to be effective in animal models of septic shock. 8 Patients with either very high ACE2 levels (such as in diabetes or cardiovascular disease) or very low levels (animal models of hypertension) can have an abnormal immune response and pulmonary inflammation.…”

Section: Angiotensin-converting Enzyme 2 (Ace2) Receptormentioning

confidence: 99%

COVID-19 in children and altered inflammatory responses

2020

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“…Binding of the Ang-(1-7) to the Mas receptor antagonizes many of the deleterious effects of Ang II, to the point that ACE2/Ang-(1-7)/Mas receptor is considered the branch of the RAS with counter-regulatory properties for the ACE/Ang II/Ang II type 1 receptor axis. 11,12 Thus, there recently has been a focus on identifying small molecules readily filtered by the glomerulus and able to modulate the ACE2/Ang-(1-7)/Mas receptor axis, and beneficial effects of treatment with Ang-(1-7) have been reported in murine models of diabetes. [13][14][15][16][17] The administration of Ang-(1-7) ameliorated type 2 diabetes in rats by improving insulin signaling and limiting hyperglycemia.…”

mentioning

confidence: 99%

Addition of cyclic angiotensin-(1-7) to angiotensin-converting enzyme inhibitor therapy has a positive add-on effect in experimental diabetic nephropathy

Cassis

Locatelli

Corna

et al. 2019

Kidney International

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The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research

Cited by 274 publications

References 0 publications

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

COVID-19 in children and altered inflammatory responses

Addition of cyclic angiotensin-(1-7) to angiotensin-converting enzyme inhibitor therapy has a positive add-on effect in experimental diabetic nephropathy

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