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Review
. 2007 May;212(1):1-11.
doi: 10.1002/path.2162.

The emerging role of ACE2 in physiology and disease

I Hamming  1 , M E Cooper, B L Haagmans, N M Hooper, R Korstanje, A D M E Osterhaus, W Timens, A J Turner, G Navis, H van Goor
Affiliations
Review

The emerging role of ACE2 in physiology and disease

I Hamming et al. J Pathol. 2007 May.

Abstract

The renin-angiotensin-aldosterone system (RAAS) is a key regulator of systemic blood pressure and renal function and a key player in renal and cardiovascular disease. However, its (patho)physiological roles and its architecture are more complex than initially anticipated. Novel RAAS components that may add to our understanding have been discovered in recent years. In particular, the human homologue of ACE (ACE2) has added a higher level of complexity to the RAAS. In a short period of time, ACE2 has been cloned, purified, knocked-out, knocked-in; inhibitors have been developed; its 3D structure determined; and new functions have been identified. ACE2 is now implicated in cardiovascular and renal (patho)physiology, diabetes, pregnancy, lung disease and, remarkably, ACE2 serves as a receptor for SARS and NL63 coronaviruses. This review covers available information on the genetic, structural and functional properties of ACE2. Its role in a variety of (patho)physiological conditions and therapeutic options of modulation are discussed.

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Figures

Figure 1
Figure 1
Schematic diagram of the renin–angiotensin–aldosterone system which shows the role of ACE and ACE2 in the metabolism of the various angiotensin peptides. Modified from Warner et al 101, with permission
Figure 2
Figure 2
The domain structure of somatic and testis ACE, ACE2, and collectrin. Each protein is a type I integral membrane protein with a cleaved signal peptide (black), an N‐terminal ectodomain, a transmembrane domain (blue in ACE; red in ACE2 and collectrin), and a C‐terminal cytoplasmic domain. Somatic ACE contains two HEMGH zinc binding active sites, while testis ACE and ACE2 contain a single HEMGH motif. Collectrin lacks a HEMGH motif. The ectodomain of ACE2 (yellow) is more similar to the N‐terminal domain of somatic ACE, while its juxtamembrane stalk, and transmembrane and cytoplasmic domains are more similar to collectrin. The numbers indicate the amino acid residues in each protein. Modified from Turner and Hooper 102, with permission
Figure 3
Figure 3
Immunohistochemical staining pattern of ACE2 in several organs. In the healthy human heart (A), ACE2 is expressed in cardiomyocytes (closed arrow), vascular endothelium (arrowhead), and smooth muscle cells (open arrow). In rat heart (B), ACE2 is predominantly expressed in vascular endothelium (arrowhead). (C) ACE2 expression in human small intestine (jejunum); abundant staining can be found in the brush border of enterocytes (arrow). In human aorta (D), ACE2 is expressed in the endothelium (arrowhead) and vascular smooth muscle cells (open arrow). In healthy human lung (E), ACE2 is present in alveolar epithelial cells (arrow) and in capillary endothelial cells (arrowhead). In human placenta (F), positive staining for ACE2 is found in the placental villi [syncytiotrophoblast, cytotrophoblast, vascular endothelium (arrowhead), and smooth muscle cells]
Figure 4
Figure 4
Immunohistochemical staining pattern of ACE2 in the kidney. In the healthy human kidney (A), ACE2 is predominantly present in the brush border of proximal tubular cells (arrow) and to a lesser extent in the glomerular visceral and parietal epithelium. In rat kidney (B), ACE2 is predominantly found in glomeruli and to a lesser extent in distal tubules (open arrow). In mouse kidney (C), the distribution pattern of ACE2 is comparable to human kidney with predominant expression in proximal tubules (arrow). ACE2 is also expressed during human nephrogenesis (gestational age 16 weeks) (D)
Figure 5
Figure 5
Alignment of amino acid sequences of ACE2 from human, macaque (Mf), cat (Felis), rat (Rn), and mouse (Mumu) critical to SARS‐CoV spike protein interactions
Figure 6
Figure 6
IFN‐gamma down‐regulates ACE2 expression in Vero E6 cells. ACE2 expression was determined by Facs analysis after treatment with TNF‐α (A), IFN‐γ (B), and IFN‐γ combined with TNF‐α (C), all at 48 h, or Vero E6 cells incubated for 96 h in the presence of IFN‐γ combined with TNF‐α (D). Dotted lines represent cytokine‐treated cells, while thick lines represent mock‐treated control cells. The shaded areas represent background staining. Modified from de Lang et al 94, with permission
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