Angiotensin-converting enzyme 2 and kidney diseases in the era of coronavirus disease 2019

Figures

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  Figure 1.. A schematic of the renin-angiotensin system (RAS) components and their modes of action. Renin converts angiotensinogen to angiotensin I (Ang I), which is subsequently cleaved by angiotensin-converting enzyme (ACE) to form Ang II. Ang II binds to its cognate G-protein-coupled receptor, angiotensin II type 1 receptor (AT1R), playing as a major effector molecule of classic RAS such as water and salt retention, vasoconstriction, and proliferative, proinflammatory, and profibrotic processes. ACE2 hydrolyzes Ang I and Ang II to Ang 1–9 and Ang-(1–7), respectively, although the enzyme efficacy for Ang II is 400-fold greater for Ang I. Angiotensin-converting enzyme 2 (ACE2) cleaves Ang II to generate Ang-(1-7), which binds to another G-protein-coupled receptor, Mas receptor (MasR). The activation of MasR is associated with abrogation of pathogenic processes medicated by AT1R, in large, counterbalances the classic RAS activation to prevent target organ damage. Ang-(1-7) is also a substrate of ACE, which is converted to an inactive metabolite. Both Ang II and Ang-(1-7) are reported to activate angiotensin II type 2 receptor (AT2R), resulting in the effect similar to MasR activation. While…

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  Figure 2.. A schematic showing the molecular structures of angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and the ACE2-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complex. Although ACE2 is homologous to ACE. But, ACE2 has only a single active site, whereas ACE possesses 2 enzymatically active sites. Similar to ACE, the N-terminus of ACE2 is a protease domain (PD, colored in green) that is exposed to extracellular surfaces, acting as a zinc metalloprotease. The C-terminus of ACE2 is a transmembrane domain with a cytosolic tail that has no similarity with ACE. It is referred to as collectrin-like domain (colored in purple), as it is a homolog of collectrin, a protein expressed in the kidney. The interaction between receptor binding domain of viral spike protein and PD of host ACE2 is known to be crucial for viral entry of SARS-CoV in early 2000s, and more recently, SARS-CoV-2. Compared to SARS-CoV, several mutations in amino acid residues in the interface between SARS-CoV-2 and ACE2 were reported, resulting in the increase of binding affinity. RBD, receptor binding domain.

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  Figure 3.. A schematic of proteolytic angiotensin-converting enzyme 2 (ACE2) ectodomain shedding after angiotensin II (Ang II)-induced TNF-α converting enzyme (TACE) activation. Activation of angiotensin II type 1 receptor (AT1R) by Ang II leads to superoxide generation, which in turn enhances phosphorylation of p38-mitogen-activated protein kinase (MAPK). Phosphorylated p38 MAPK is critical for the activation of TACE, via phosphorylation of a cytosolic residue. Activated TACE cleaved ACE2 from extracelluar surface, resuling in the shedding of ACE2 ectodomain. Ang-(1-7), angiotensin-(1-7); MasR, Mas receptor; ROS, reactive oxygen species.