Circulation Journal

Official Journal of the Japanese Circulation Society

REVIEW
http://www. j-circ.or.jp

Multiple Functions of Angiotensin-Converting

Enzyme 2 and Its Relevance
in Cardiovascular Diseases
Keiji Kuba, MD, PhD; Yumiko Imai, MD, PhD; Josef M. Penninger, MD

Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system, and functions as
the key SARS coronavirus receptor and stabilizer of neutral amino acid transporters. ACE2 catalyzes the conversion
of angiotensin II to angiotensin 1–7, thereby counterbalancing ACE activity. Accumulating evidence indicates that
the enzymatic activity of ACE2 has a protective role in cardiovascular diseases. Loss of ACE2 can be detrimental,
as it leads to functional deterioration of the heart and progression of cardiac, renal, and vascular pathologies. Re-
combinant soluble human ACE2 protein has been demonstrated to exhibit beneficial effects in various animal mod-
els, including cardiovascular diseases. ACE2 is a multifunctional enzyme and thus potentially acts on other vasoac-
tive peptides, such as Apelin, a vital regulator of blood pressure and myocardium contractility. In addition, ACE2 is
structurally a chimeric protein that has emerged from the duplication of 2 genes: homology with ACE at the carboxy-
peptidase domain and homology with Collectrin in the transmembrane C-terminal domain. ACE2 has been impli-
cated in the pathology of Hartnup’s disease, a disorder of amino acid homeostasis, and, via its function in amino acid
transport, it has been recently revealed that ACE2 controls intestinal inflammation and diarrhea, thus regulating the
gut microbiome. This review summarizes and discusses the structure and multiple functions of ACE2 and the rele-
vance of this key enzyme in disease pathogenesis.   (Circ J 2013; 77: 301 – 308)

Key Words: Angiotensin-converting enzyme 2 (ACE2); Amino acid transporter; Acute respiratory distress syndrome
(ARDS); Renin-angiotensin system (RAS); Severe acute respiratory syndrome (SARS)

A
ngiotensin-converting enzyme 2 (ACE2) as a human
homolog of ACE was discovered in 2000,1,2 and later
revealed to constitute a new enzymatic pathway re-
quired for the generation of angiotensin (Ang) 1–7 from Ang
II. Before the discovery of ACE2, the enzymatic pathway to
degrade Ang II to Ang1–7 was assumed to be mediated by
prolyl-endopeptidase,3 prolyl-carboxypeptidase,4 thimet oligo-
peptidase5 and/or neprilysin6 (Figure 1). ACE2 consists of
805 amino acids and is a type I transmembrane glycoprotein
with a single extracellular catalytic domain. The human and
rodent ACE2 genes map to the X chromosome.7,8 Like ACE,
ACE2 has 2 domains: the amino-terminal catalytic domain
and the carboxy-terminal domain (Figure 2). The catalytic
domain has 1 active site – the zinc metallo-peptidase domain
– and shows 41.8% sequence identity with the amino domain
of ACE.1,2 The carboxy-terminal domain of ACE2 shows 48%
sequence identity with Collectrin9 (Figure 2), a non-catalytic
protein recently shown to have a critical role in amino acid
reabsorption in the kidney,10,11 pancreatic β-cell proliferation,12
and possibly insulin exocytosis.13 ACE2 is predominantly
expressed in the heart, kidneys and testes, and at lower levels
in a wide variety of tissues, particularly the colon and lung.2 In
the heart, ACE2 is expressed in the endothelium2 and cardio-
myocytes.14 In the kidney, ACE2 distributes to the luminal
surface of tubular epithelial cells,1,2 which is in contrast to
ACE, which appears to be evenly distributed between the api-
cal and basolateral membranes in polarized cells.15 Indeed, the
efficacy of severe acute respiratory syndrome-associated coro-
navirus (SARS-CoV) infections was 10-fold increased when
the virus was applied to the apical surface of ACE2-expressing
cells in vitro.16
Carboxypeptidase Domain of ACE2
ACE2 catalyzes enzymatic reactions by utilizing zinc ions,
coordinated by conserved histidines within the active site (the
HEXXH motif), to facilitate a nucleophilic attack on the car-
bonyl bond of the substrate by a water molecule, forming a
non-covalently bound intermediate. Structural analyses of na-
tive ACE2 compared with ACE2 in the presence of an inhibi-
tor have revealed a large “hinge-bending” motion, in which
the catalytic subdomains I and II of the peptidase domain ex-
hibit open-to-close transitions. This movement appears to be
induced by binding of the inhibitor and repositions key resi-

Received December 13, 2012; revised manuscript received January 4, 2013; accepted January 7, 2013; released online January 18, 2013
Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Akita (K.K., Y.I.),
Japan; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna (J.M.P.), Austria
Mailing address: Keiji Kuba, MD, PhD, Department Biological Informatics and Experimental Therapeutics, Akita University Graduate
School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.   E-mail: kuba@med.akita-u.ac.jp
ISSN-1346-9843   doi: 10.1253/circj.CJ-12-1544
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal Vol.77, February 2013

302 KUBA K et al.

dues for catalysis.17

Figure 1. Current view of angiotensin-converting enzyme 2
(ACE2) in the renin-ngiotensin system. ACE2 was identified as
a major angiotensin 1–7 (Ang1–7)-forming enzyme. Angioten-
sin I (Ang I) serves as a substrate for both ACE and ACE2.
Ang II is known to act as a vasoconstrictor in vivo. Both ACE
and ACE2 are involved in the production of Ang1–7, which
binds the Mas receptor and induces vasodilation.
Despite their similarities, ACE and ACE2 function differ-
ently; ACE releases a C-terminal dipeptide from its substrate
(dipeptidylpeptidase), whereas ACE2 cleaves a single amino
acid (monocarboxypeptidase).1,2 ACE2 catalyzes peptides,
with a substrate preference for hydrolysis between proline and
a hydrophobic or basic C-terminal residue.18 Whereas ACE
converts AngI to the potent vasoconstrictor Ang II,19 ACE2
cleaves AngI to generate the presumably inactive Ang1–9
peptide,1,2 which then can be converted to the vasodilator
peptide Ang1–7 by ACE or other peptidases.1 Importantly,
ACE2 directly metabolizes Ang II to generate Ang1–7 with
much higher efficiency than converting AngI to Ang1–918
(Figures 1,3). The resolution of the ACE2 crystal structure
revealed that these differences in substrate specificity are a
result of the smaller binding pocket in ACE2 where arginine-
273 makes a salt-bridge with the C-terminus of the substrate,
whereas in ACE this residue is substituted by a smaller gluta-
mine.17 Although enzymes were known to generate Ang1–7
(eg, prolyl-endopeptidase 24.26,3 thimet oligopeptidase,5 and
neprilysin6), ACE2 is clearly the main enzyme that catalyzes
this reaction in vitro and in vivo.1,2,18 The ACE2 product,
Ang1–7 peptide, has been shown to interact with the G pro-
tein-coupled receptor Mas to mediate its vasoprotective ef-
fects.20,21 ACE2 also acts on the C-terminal amino acids of the
peptides Apelin-13 and Apelin-36 with high catalytic effi-
ciency in vitro18 (Figure 4). Apelin is synthesized as a 77
amino acid pre-pro-hormone, which is processed into the 36
amino acid peptide Apelin-36; further proteolytic cleavage
generates Apelin-13.22,23 Systemic administration of Apelin-
13 induced hypotension in rats and mice.24,25 Interestingly,
modification of the C-terminal residue of Apelin-13 (F13A)
resulted in a loss of its hypotensive function and antagonism
of wild-type Apelin-13,26 implicating ACE2 in the metabolism
of Apelin peptides.

Figure 2. Angiotensin-converting enzyme 2 (ACE2) is a chimeric protein with homology to both ACE and Collectrin. Each protein
is a type I integral protein with a signal peptide, depicted in gray, and a transmembrane domain shown in black. The zinc-binding
motif (HEMGH) repeats twice in ACE and once in ACE2, and is located within the homology region denoted by the yellow box.
Regions of homology between ACE2 and Collectrin are denoted in green, whereas homology of ACE and ACE2 is shown in blue.
The numbers refer to the amino acids in each human protein.

Circulation Journal Vol.77, February 2013

Multiple Functions of ACE2 303

Figure 3. Multiple roles of angiotensin-converting enzyme 2 (ACE2) determined in genetic experiments. (A) ACE2 is a potent
negative regulator of the renin-angiotensin system, catalyzing the conversion of Ang II to Ang1–7. ACE2 is an essential receptor
for the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) (B) and also interacts with amino acid transporters
and integrins (C).

Figure 4. Domain structure and molecular functions of angiotensin-converting enzyme 2 (ACE2). The N-terminus extracellular
domain of ACE2 (blue) functions as a carboxypeptidase, SARS receptor, and integrin substrate, while the C-terminus Collectrin
region (green) is crucial for binding to the neutral amino acid transporters B0AT1. SARS, severe acute respiratory syndrome; TM,
transmembrane region.

ACE2 as a SARS Receptor and
an Integrin Substrate
Although ACE2 functions as a mono-carboxypeptidase to cat-
alyze Ang II cleavage, further studies demonstrated that ACE2
has additional biological functions. In 2003, the epidemic of
SARS threatened the world and ACE2 was identified as a
functional receptor for the causative pathogen, SARS-CoV.27,28
Interaction of SARS-CoV with ACE2 is initiated via trimers
of the SARS Spike protein, which extends into a hydrophobic
pocket of the ACE2 catalytic domain.29 This ACE2-Spike in-
teraction leads to endocytosis of virus particles through in-
ternalization with ACE2, induces the fusion of virus and host
cells, and establishes SARS-CoV infection. However, this
process does not require or affect the peptidase activity of
ACE2, because cells expressing catalytic inactive mutants of

Circulation Journal Vol.77, February 2013

304
ACE2 are still permissive for SARS-CoV infection, and ACE2
substrates are still accessible to the catalytic pocket of ACE2
when the SARS Spike protein is bound. Furthermore, in the
structure of SARS Spike-bound ACE2, the catalytically-active
site of ACE2 was not blocked by the SARS Spike protein.29
Thus, ACE2 functions as a SARS receptor independently of
its peptidase activity (Figure 3).
It has been reported that ACE2 is internalized together with
SARS-CoV upon infection and that endocytosis is essential for
virus entry.30,31 The internalization can take place even when
recombinant SARS Spike protein, the SARS-CoV surface li-
gand for receptor binding, interacts with ACE2.27,32 In addition,
it has been suggested that shedding of the ACE2 ectodomain
is involved in the transmembrane domain internalization for
further virus particle-host cell fusions.31–33 Clathrin-dependent
and -independent entry of SARS-CoV into target cells have
been proposed.31,32 However, the role of the cytoplasmic tail of
ACE2 is controversial; for instance, deletion of the cytoplas-
mic tail of ACE2 did not affect SARS-CoV entry in 1 experi-
mental setup,31 whereas it attenuated SARS-CoV entry in an-
other study.33 Apart from being the SARS receptor, Lin et al
biochemically purified the integrin β1 as an ACE2 interacting
molecule from homogenates of failing human hearts,34 and a
recent study has shown that the ectodomain of ACE2 binds to
integrin β1 and integrin α5 (Figure 3), suggesting that ACE2
could be an integrin substrate.35 Thus, ACE2 might have a role
in integrin-mediated signaling in cardiovascular diseases.
“Collectrin” Domain of ACE2 Regulates Amino
Acid Transporter Expression
Structural homology searches show that ACE2 is a chimeric
protein that has emerged from the duplication of 2 genes: ho-
mology with ACE at the catalytic domain and homology with
Collectrin (gene name: transmembrane protein 27 [Tmem27])
in the transmembrane C-terminal domain. Transcriptome anal-
ysis from partially nephrectomized rats identified Collectrin as
an upregulated gene in regenerating collecting ducts.9 Collec-
trin shares 47.8% identity with the C-terminus of ACE2, but,
unlike ACE2, lacks an active carboxypeptidase catalytic do-
main9 (Figure 2). An initial report indicated that Collectrin
localizes to the cytoplasm of collecting duct epithelial cells.9
However, gene-targeting studies in mice showed that Collec-
trin is an essential regulator of neutral amino acid transporters
and is predominantly localized in the brush borders of proxi-
mal tubular epithelial cells.10 Excessive amounts of neutral
amino acids (tyrosine and phenylalanine) appear in the urine
of Collectrin knockout mice. Biochemical studies reveal that
Collectrin binds to the B0AT1 neutral amino acid transporter
(and probably other neutral amino acid transporters) in the
kidney where it controls expression of these transporters on the
cell surface that are required for amino acid reabsorption in the
proximal tubules.10,36 Despite its structural similarity, ACE2
does not bind to amino acid transporters in kidneys. Instead, it
is highly expressed on the luminal surface of small intestinal
epithelial cells, and in the gut, ACE2 binds to the B0AT1
amino acid transporter and contributes to the absorption of
dietary neutral amino acids37 (Figure 3). Importantly, the pep-
tidase activity of ACE2 is not necessary for pairing with the
amino acid transporter (Figure 4).
ACE2 as a Negative Regulator of the RAS
in the Cardiovascular System
Genetic analysis in rat models of hypertension have mapped
Circulation Journal Vol.77, February 2013
KUBA K et al.
Ace2 as a quantitative trait locus) onto the X chromosome.
Those hypertensive rats show reduced ACE2 transcripts and
protein expression in both heart and kidney.7 Transgenic ACE2
overexpression in the vessels of SHRSP rats reduces blood
pressure (BP) and improves endothelial function,38 and neuro-
nal overexpression of ACE2 also attenuates hypertension.39,40
In humans, several studies have shown a strong association of
ACE2 polymorphisms to hypertension in female Chinese pa-
tients with metabolic syndrome,41 essential hypertension42–45
or diabetes-associated hypertension.46 Thus, together with bio-
chemical data that ACE2 degrades Ang II to generate Ang1–7,
it appears that ACE2 plays a profound role in controlling BP.
However, genetic inactivation of ACE2 using homologous
recombination results in no apparent alterations in BP in the
basal state.7 In another line of ACE2 knockout mice, BP was
significantly increased following Ang II infusions,47 in sharp
contrast to the spontaneous hypotension observed in ACE
knockout mice,48 suggesting that, in addition to the Ang II
system, ACE2 might regulate BP through other peptide sys-
tems, such as bradykinin and/or Apelin. Nevertheless, exoge-
nous supplementation of ACE2 by gene transfer decreased BP
in SHR hypertensive rats,38 and recombinant ACE2 treatment
attenuated Ang II-induced hypertension specifically.49 Thus,
ACE2 clearly must function as a negative regulator of the RAS
in BP control. In addition to BP regulation, ACE2 delivery has
also shown beneficial effects on atherosclerosis in animal mod-
els, suggesting that ACE2 confers endothelial protection.50,51
ACE2 is highly expressed in the heart and in multiple stud-
ies ACE2 has been reported to function as a regulator of heart
failure. The key finding has been that ACE2 null mice display
impaired cardiac contractility, which is associated with aging
and/or cardiac pressure overload in several different lines of
ACE2 knockout mice.7,52,53 Impaired cardiac contractility cor-
related with elevated cardiac and plasma Ang II levels, and
Ace and Ace2 (double-knockout) mice or treatment with AT1
receptor blockers reversed the cardiac phenotype of ACE2
knockout mice.7,52,53 Similarly, in myocardial infarction, loss
of ACE2 accelerates maladaptive left ventricular remodel-
ing.54 Mechanistically, the age-dependent cardiomyopathy in
ACE2 knockout mice is likely mediated by Ang II-induced
oxidative stress and induction of inflammation through AT1
receptor downstream PI3K (phosphatidylinositol-3-kinase)
signaling.55
In addition to the counterbalancing effects between ACE
and ACE2, it has been proposed that ACE2 might control heart
functions via Ang1–7 and Apelin. In particular, treatment with
Ang1–7 peptide can improve myocardial performance, cardiac
remodeling, and even survival in rodent heart failure models,
including ischemia/reperfusion injury, myocardial infarction,
and hypertension-induced cardiomyopathy.56,57 The selective
Mas receptor ligand, AVE-0991, has actions similar to the car-
dioprotective effects of the Ang1–7 peptide,58 and Mas receptor
knockout mice display reduced heart contractility,21 suggesting
that Ang1–7 via its putative receptor Mas mediates these ef-
fects. Functional crosstalk between ACE2 and the Ang1–7-
Mas system has been recently demonstrated experimentally;
in pressure overload-induced heart failure, the Ang1–7 peptide
can rescue the systolic dysfunction present in Ace2 null mice
and attenuate the increase in NADPH oxidase activation.59
In addition to Ang II, ACE2 also acts on the peptides Ape-
lin-13 and Apelin-36 with high catalytic efficacy in vitro.18
Apelin-13 and Apelin-36 are generated by proteolytic process-
ing of a 77 amino acid Apelin pre-prohormone.22,23 Although
systemic administration of Apelin peptides triggers hypoten-
sion in rats and mice,23,24 Apelin and APJ (Apelin receptor)
Multiple Functions of ACE2
knockout mice both showed little alterations in BP at baseline.
Interestingly, Apelin knockout mice showed aging- or stress-
associated cardiac contractility defects, similar to the heart
phenotype of ACE2 knockout mice,60 suggesting that ACE2
and Apelin may share the same signaling pathway to control
heart functions. Although further studies are required to vali-
date the proposed crosstalk, in humans both ACE2 and Apelin
polymorphisms are associated with parameters of left ven-
tricular hypertrophy61 and BP responses to potassium supple-
mentation,62 and soluble ACE2 activity is increased in patients
with myocardial dysfunction and correlates with disease sever-
ity,63 implicating physiological roles of ACE2 and Apelin in
patients.
ACE2 in the Kidney
In 2002, it was reported that ACE2 is abundantly expressed in
the kidney,7 and the activity of ACE2 is even higher in the
kidney cortex than in heart tissue.64 ACE2 has emerged as a
protective molecule against kidney diseases in the context of
negative regulation of the RAS.65,66 For instance, deletion of
Ace2 leads to spontaneous late-onset nephrotic glomeruloscle-
rosis67 and accelerates diabetic kidney injury in both Akita
diabetic mice68 and streptozocin-induced diabetic mice.69 In
line with these results, pharmacological ablation of ACE2 by
MLN-4760 has resulted in increased albuminuria and glo-
merular pathology in the kidneys of db/db diabetic mice and
streptozocin-induced diabetic mice.70,71 These phenotypes are,
at least in part, dependent on Ang II signaling and can be
rescued by AT1 receptor blockade.70,71 Thus, these data defi-
nitely indicate that ACE2 is renoprotective. In hypertensive
SHR rats, with the onset of hypertension, the tubular expres-
sion of ACE2 in the kidneys is downregulated compared with
control rats.71,72 Diabetic nephropathy in experimental models
has also been shown to alter both the glomerular and tubular
expression of ACE2, and recently, the involvement of ACE2
in glucose transport was implicated.72 There is an early in-
crease in ACE2 expression and activity in the kidneys of dia-
betic db/db64,71 and Akita68 mice. The highest expression of
ACE2 mRNA found in renal proximal tubules was, however,
significantly reduced in the tubules from diabetic rats.73 Thus,
reduced ACE2 expression might contribute to the pathogen-
esis and progression of kidney diseases.73–75 Renal expression
of ACE2 most likely plays a profound role in controlling local
RAS rather than regulating systemic BP. Therefore, ACE2
counterbalances ACE function, negatively regulates Ang II
levels, and thereby controls local kidney homeostasis.
ACE2 in the Lung
Acute respiratory distress syndrome (ARDS) is the most severe
form of acute lung injury, which affects approximately 1 million
individuals worldwide/year and has a mortality rate of at least
30–50%.76,77 ARDS can be triggered by multiple diseases, such
as sepsis, aspiration, trauma, acute pancreatitis, or pneumonias
following infections with SARS-CoV or the avian and human
influenza viruses.78,79 Previous studies showed a correlation
between an ACE insertion/deletion polymorphism and the se-
verity of ARDS in humans,78,79 and ACE inhibitor treatments
in rodent ARDS models80 suggested that the RAS could have a
role in ARDS/acute lung injury. Intriguingly, despite having a
normal lung structure and function, Ace2 knockout mice ex-
hibit very severe pathology of ARDS/acute lung injury com-
pared with wild-type control mice, defined by enhanced vascu-
lar permeability, increased lung edema, neutrophil accumulation,
Circulation Journal Vol.77, February 2013
305
and markedly worsened lung function.81 AT1 blocker treatment
or additional Ace deficiency on an Ace2 knockout background
rescues the severe acute lung injury phenotype of Ace2 single
mutant mice.81 Importantly, treatment with catalytically-active,
but not enzymatically-inactive, recombinant ACE2 protein im-
proved the symptoms of acute lung injury in wild-type mice, as
well as in Ace2 knockout mice.81 Furthermore, in a recent study
of large animals in a sepsis ARDS model, recombinant ACE2
protein significantly improved the respiratory failure and in-
creased the oxygen levels of ARDS-affected pigs.82 Thus, in
acute lung injury, ACE, Ang II, and the AT1 receptor function
as lung injury-promoting factors, while the negative regulation
of Ang II levels by ACE2 protects against lung injury.81 More-
over, in other lung injury models, such as bleomycin-induced
lung fibrosis and monocrotaline-induced pulmonary hyperten-
sion, ACE2 has been recently shown to protect against chronic
lung injury, fibrosis, and pulmonary vasoconstriction.83,84 These
results indicate that ACE2 may serve as an entirely novel
therapeutic for chronic lung diseases as well as acute lung in-
jury. The efficacy of recombinant soluble human ACE2 protein
on acute lung failure is currently being tested in phase II human
clinical trials.
During 2003, a newly identified illness termed “severe acute
respiratory syndrome (SARS)” spread rapidly worldwide. In-
ternational cooperative teams swiftly isolated a novel corona-
virus as the SARS pathogen (SARS-CoV) and determined the
SARS-CoV genome sequence.85,86 Surprisingly, ACE2 was
identified by co-immunoprecipitation techniques as a func-
tional receptor in vitro.28 Subsequently, in a SARS infection
model in Ace2 knockout mice, ACE2 was indeed identified as
the essential receptor for SARS infections in vivo.27 One mys-
tery of SARS-CoV is why, in contrast to other coronaviruses,
such infections trigger severe lung disease with such high
mortality. Accumulating evidence indicates that severe SARS
infections are dependent on the burden of viral replication, as
well as on the immunopathological consequences of the host
response.87,88 In addition to aberrant activation of the immune
system, our own studies have implicated direct involvement of
ACE2 in SARS pathogenesis. Intriguingly, both SARS-CoV
infection and challenge with recombinant SARS Spike protein
triggered a marked downregulation of ACE2 expression in
both lungs and cell culture.27 Thus, SARS-CoV-infected or
Spike protein-treated mice resemble Ace2 knockout mice.
Similar to Ace2 mutant mice, Spike-treated wild-type mice
show markedly more severe pathology in acute lung injury.27
Therefore, downregulation of the SARS receptor, ACE2, by
SARS-CoV infection activates the RAS and contributes to the
pathogenesis of severe ARDS/acute lung injury in SARS.
ACE2 in Hartnup’s Disorder and Intestinal
Epithelial Immunity
The Collectrin gene is located in immediate proximity to the
Ace2 locus on the X chromosome and both genes share similar
transcription factor binding sites. Collectrin is expressed in
β-cells of the pancreas under the transcriptional control of
hepatocyte nuclear factor 1, where it was implicated in insulin
exocytosis or β-cell proliferation.12,13 Surprisingly, using gene-
targeting studies of Collectrin in vivo, Collectrin turned out to
be a critical binding partner for neutral amino acid transporters.
Collectrin physically associates with numerous apical amino
acid transporters in the kidney and controls their expression
and transport functions.10 As a consequence, Collectrin mutant
mice exhibit a marked defect in the reabsorption of amino
acids in the proximal tubules of the kidneys. Biochemically,
306
Collectrin binds to B0AT1-family amino acid transporters and
controls polarized expression of these transporters on the cell
surface.10,36
Hartnup’s disorder is a hereditary familial disease charac-
terized by a pellagra-like light-sensitive rash, cerebellar ataxia,
emotional instability, and amino aciduria.89 Gene mutations in
the B0AT1 (Slc6a19) neutral amino acid transporter have been
identified as a cause of Hartnup’s disorder.90 Despite the lack
of mutations of ACE2 and Collectrin in Hartnup’s disease,
among the known human Hartnup mutations in B0AT1, the
A69T and R240Q missense mutants were shown to be func-
tionally linked to ACE2 and Collectrin.37,90 In addition to
Hartnup’s disorder, a recent study by our group revealed that
ACE2 regulates intestinal epithelial immunity by controlling
amino acid homeostasis, expression of antimicrobial peptides,
and the ecology of the gut microbiome.91 The finding can
molecularly explain why amino acid malnutrition can cause
intestinal inflammation and diarrhea. Because such RAS-in-
dependent functions of ACE2 have not yet been observed in
cardiovascular systems, such as hearts, kidneys, and blood
vessels, further studies are warranted.
Conclusions
ACE2 has been established as an in vivo negative regulator of
systemic and local RAS function through its peptidase activity.
The carboxypeptidase activity of ACE2 limits the availability
of Ang II, generates counter-regulatory vasodilator peptides
such as Ang1–7, and may also act on other peptide systems
such as Apelin or dynorphin. Importantly, ACE2 has also been
identified as the key SARS receptor and plays a protective role
in SARS-mediated ARDS. These findings led to the develop-
ment of recombinant human ACE2 protein as a potential novel
medicine for the treatment of acute respiratory failure, which is
now being tested in a clinical trial. During the course of study-
ing ACE2 function, we also made an entirely unexpected find-
ing: ACE2 and Collectrin are essential for the expression of
amino acid transporters, which added another level of complex-
ity to this key regulator of the RAS system. Understanding the
complexity and molecular crosstalk of the RAS system will not
only broaden our knowledge of the evolution and biology of the
cardiovascular system,92,93 but also lead to the development of
new and refined therapeutic strategies for various diseases.
Acknowledgments
K.K. is supported by the Funding Program for Next Generation World-
Leading Researchers from the Japan Society for the Promotion of Science
(NEXT Program), and the KAKEN (22390155) from the Japanese Min-
istry of Science. Y.I. is supported by the NEXT Program, KAKEN,
Takeda Foundation and Uehara Foundation. J.M.P. is supported by IMBA,
the Austrian Ministry of Science and Education, an Advanced ERC grant,
and the LeDucq Foundation.
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