1. Introduction
The renin-angiotensin system (RAS) is involved in the regulation of fluids in
the human body [1], and is found in the circulatory system, and local tissues in
the form of autocrine and paracrine factors [2]. It helps to regulate the
circulatory [3, 4, 5], renal [6, 7], and digestive systems [8, 9]. The RAS is
composed of an enzyme cascade. Angiotensinogen is converted to angiotensin I (Ang
I) under the action of renin, and then transformed into angiotensin II (Ang II) due
to the effect of the angiotensin-converting enzyme (ACE). Ang II is an important
active peptide in the RAS and is one of the most potent vasoconstrictors [10, 11]. It functions through Ang II type 1 receptors (AT) and
Ang II type 2 receptors (AT) and plays an important role in the
cardiovascular system, and in kidney, skeletal muscle, liver, and adipose
tissues. Ang II promotes salt and water reabsorption [12], vasoconstriction,
inflammation, sympathetic nerve activation, and oxidative stress by activating
AT [13, 14]. New members of the RAS are constantly being discovered.
Angiotensin-converting enzyme 2 (ACE2) was the first homologous gene cloned from
human ACE in 2000 [15, 16]. ACE2 can catalyze the conversion of Ang II into
angiotensin (1-7) [Ang-(1-7)], and Ang I into angiotensin (1-9) [Ang-(1-9)],
which can be converted to Ang-(1-7) by ACE or neutral endopeptidase (NEP).
Ang-(1-7) can also be directly produced by Ang I under the action of NEP, and
then acts through Mas receptors (see Fig. 1). The ACE2/Ang-(1-7)/Mas axis can
inhibit the effects of ACE/Ang II/AT in the myocardium, blood vessesls,
kidney, adipose tissue and other organs. Both the ACE/Ang II/AT axis and the
ACE2/Ang-(1-7)/Mas axis participate in the regulation of glucose metabolism. The
ACE2/Ang-(1-7)/Mas axis has been shown to prevent the unfavorable metabolic
effects of the ACE/Ang II/AT axis [17, 18]. At present, the
ACE2/Ang-(1-7)/Mas axis is being extensively studied in metabolic diseases such
as diabetes [19, 20]. The ACE2/Ang-(1-7)/Mas axis may become a potential
therapeutic target in the treatment of diabetes. Therefore, the role of the
ACE2/Ang-(1-7)/Mas axis in glucose metabolism is the subject of this review.
Fig. 1.
Simplified view of ACE/Ang II/AT axis and ACE2/Ang-(1-7)/Mas
axis. Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1-7), angiotensin-(1-7);
Ang-(1-9), angiotensin-(1-9); Mas, Mas receptor; ATR, Ang II type 1
receptor; ATR, Ang II type 2 receptor; ACE, angiotensin-converting enzyme;
ACE2, angiotensin-converting enzyme 2; NEP, neutral endopeptidase; PEP, prolyl
endopeptidase; TOP, thimet oligopeptidase.
The literature was searched extensively through the PubMed database with the
combinations of the key words: ACE2/Ang-(1-7)/Mas axis,
angiotensin-converting enzyme 2,
angiotensin-(1-7), Mas receptors, glucose metabolism, diabetes (see Fig. 2). The
included literatures were published from 1996 to 2021. In order to prevent
omissions, relevant articles in the reference list of the primary literatures
were included. Inclusion criteria were: (1) diabetes-related animal models or
patients; (2) experimental studies related to the ACE2/Ang-(1-7)/Mas axis; (3)
researchs related to the glucose metabolism of the RAS. Exclusion criteria were:
(1) non-English language; (2) repeated reports; (3) animal models or research
unrelated to glucose metabolism in ACE2/Ang-(1-7)/Mas axis study.
Fig. 2.
Flowchart of study selection.
2. Composition of ACE2/Ang-(1-7)/Mas axis
2.1 ACE2
ACE2 is the first homologous gene of human ACE, which was cloned from
complementary DNA of human lymphoma and heart failure tissue by Donoghue et al
and Tipnis et al in 2000 [15, 16]. Its relative molecular weight is 120 kD, and
it is located at the Xp22 site of the X chromosome. ACE2, as a dedicated
mono-carboxypeptidase, can only hydrolyze one amino acid residue. ACE2 is
expressed on the cell surface, mainly in vascular endothelial cells, and the
expression of vascular smooth muscle cells is low. It is expressed to varying
degrees in the hypothalamus, heart (endothelial cells of the coronary artery),
kidney (epithelial cells of renal vessels and renal tubules), liver, spleen, and
gastrointestinal tract [15]. The main biological effect of ACE2 is the
degradation of Ang II to produce Ang-(1-7), and it acts on Ang I to generate
Ang-(1-9), which is further transformed into Ang-(1-7). The hydrolytic activity
of ACE2 on Ang II is 400 times higher than that of Ang I. It plays an important
role in myocardial protection [21, 22], fibrinolytic resistance [23] and as an
anti-atherosclerosis agent [24, 25]. Overexpression of ACE2 can inhibit oxidative
stress, inflammation and monocyte adhesion caused by Ang II [26]. Studies have
found that ACE2 overexpression can restore the functional damage of pancreatic
cells mediated by Ang II and improve glucose tolerance [27]. ACE2
deficiency can reduce the number of pancreatic cells and slow the
proliferation of cells in obese C57BL/6 mice [28]. Following ACE2 gene
therapy in diabetic db/db mice, the function of pancreatic cells was
significantly improved and insulin secretion was increased [29].
2.2 Ang-(1-7)
Ang-(1-7) is an endogenous heptapeptide. The amino acid sequence is
NH-Asp-Arg-Val-Tyr-Ile-His-Pro.
Ang-(1-7) is predominately obtained by the hydrolysis of Ang II by ACE2 [30]. It
can also be obtained from the hydrolysis of Ang I by NEP, prolyl
carboxypeptidase, and oligopeptidase. The hydrolysis by ACE2 is the main reaction
for the production of Ang-(1-7). Ang-(1-7) activates the
prostaglandin-bradykinin-nitric oxide (NO) system through the Ang-(1-7)/Mas
pathway, thereby inhibiting Ang II and negatively regulating the RAS. Ang-(1-7)
not only results in vasodilation, but also has anti-inflammatory,
anti-proliferation, and anti-fibrosis properties which contribute to ventricular
remodeling, and improve endothelial function [31, 18]. It also has
anti-arrhythmic effects, and inhibits tumor proliferation, improves glucose and
lipid metabolism, improves vascular cognitive impairment and inflammation-related
memory dysfunction [32, 33, 34]. Studies have shown that the ACE2/Ang-(1-7)/Mas axis
plays an important role in maintaining normal glucose metabolism [35, 36].
2.3 Mas receptor
The Mas receptor, a G protein-coupled receptor, contains 325 amino acid
residues, and its endogenous binding substance is Ang-(1-7) [37, 38]. Ang-(1-7)
can inhibit cellular dysfunction by promoting cell proliferation and reduce cell
apoptosis by binding to the Mas receptor [39, 40]. Proliferation of NIT-1 cells
were significantly increased after pretreatment with Ang-(1-7) in a model of
hyperglycemia by inhibiting NIT-1 cells’ proliferation, which was reversed after
the addition of the Mas receptor specific antagonist A-779. It has been shown
that Ang-(1-7) can promote cell proliferation by binding to the Mas receptor
[41]. After knocking out the Mas gene, FVB/N mice showed abnormal glucose
tolerance [42]. Mas deficiency can lead to increased plasma glucagon levels and
affect glucose homeostasis [43]. The Mas receptor itself is not an Ang II
receptor, but it can form a constitutive hetero-oligomeric complex with the
AT receptor, which interferes with the functional activity of AT and
further inhibits the effect of Ang II [44].
3. ACE2/Ang-(1-7)/Mas axis and glucose metabolism
Insulin resistance and defects in pancreatic -cell function are
involved in the pathogenesis of type 2 diabetes. Insulin resistance is
characterized by the reduction of glucose uptake by muscle and adipose tissues.
The RAS is closely related to the function of pancreatic cells. Ang II
inhibits insulin synthesis and secretion by affecting the insulin signaling
pathway. Ang-(1-7) acts through Mas receptors, and inhibits the physiological
effects of Ang II on multiple organ systems [45, 46]. The ACE2/Ang-(1-7)/Mas axis
also plays a protective role in diabetic nephropathy [47, 48, 49, 50]. Studies have shown
that nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the expression
of RAS gene in the kidney, interferes with the transcription of ACE2 and Mas
[51], and induces hypertension and kidney damage in diabetic patients. Ang-(1-7)
can counteract the pro-inflammatory effect of Ang II and protect kidney function
[52]. Through the Mas/PI3K/Akt signaling pathway, it can also enhance the
protection of vascular endothelium of diabetic patients [53].
3.1 ACE2/Ang-(1-7)/Mas axis and pancreatic cells
The ACE2/Ang-(1-7)/Mas axis can affect the structure and function of adult
pancreatic islets, promote the proliferation and differentiation of pancreatic
islet stem cells, and the regeneration of cells [54]. The
ACE2/Ang-(1-7)/Mas axis can regulate the production of pancreatic cells during
mouse embryonic development. In the mouse model, the endogenous expression levels
of Ang-(1-7) and Mas receptors were up-regulated at the late stage of mouse
embryonic pancreatic development. In a vitro culture model, Ang-(1-7) treatment
increased the ratio of cells and cells and the secretion of
insulin. It has been shown that the axis can stimulate the development of
embryonic pancreatic cells [55]. Increased glucose levels can induce activation
of the ACE2/Ang-(1-7)/Mas axis and stimulate pancreatic cells to
produce insulin [56]. Ang-(1-7) regulates insulin secretion in vivo and
in vitro by increasing intracellular cyclic adenosine monophosphate [57]. The
ACE2/Ang-(1-7)/Mas axis can improve islet cell microcirculation and inhibit the
production of islet cell nitric oxide synthase (NOS), thereby improving the
dedifferentiation of cells and exerting a protective effect [58, 59].
Xiuping et al. [58] found that the ACE2/Ang-(1-7)/Mas axis may be one of
the paracrine mechanisms of communication between pancreatic cells and
cells. Ang-(1-7) resists oxidative damage and protects pancreatic
cells [60]. The ACE2/Ang-(1-7)/Mas axis also has a protective effect on
injured pancreatic cells and reduces the production of inflammatory factors by
activating the endothelial NOS and NO signaling pathways [61]. The lack of ACE2
can reduce the number and proliferation of pancreatic cells in obese
c57bl16 mice [28].
3.2 ACE2/Ang-(1-7)/Mas axis and skeletal muscle
Skeletal muscle is the main site of insulin resistance in patients with type 2
DM. It processes more than 70% of glucose in the body. Studies have shown that
after the addition of Ang II, glucose uptake by skeletal muscle cells was
significantly reduced both in vivo and in vitro, and the phosphorylation
levels of protein kinase B (AKt) and glycogen synthase kinase3
(GSK-3) were significantly down-regulated. It is hypothesized that Ang II
activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, increases
reactive oxygen species (ROS) levels and oxidative stress, inhibits the insulin
signal transduction pathway and glucose transporter-4 (GLUT4) activity [62].
Ang-(1-7) activates the PI3K/AKt pathway of skeletal muscle endothelial cells,
increases insulin-induced glucose uptake, and improves insulin resistance through
its anti-oxidative stress effect [63]. The expression of GLUT4 and myocyte
enhancer factor (MEF) 2A was significantly reduced in skeletal muscle tissue of
ACE2 knockout mice receiving a regular diet. After Ang-(1-7) intervention, the
expression of GLUT4 and MEF 2A increased. The expression of GLUT4 and MEF 2A was
significantly decreased in wild-type mice treated with the Mas antagonist A779.
The mouse C2C12 skeletal muscle cell line was used as a model of muscle cell
differentiation in vitro. The expression of GLUT4 and MEF 2A was
significantly up-regulated at 6 h after Ang-(1-7) intervention during the process
of myoblast differentiation, and insulin-induced glucose supplementation was
increased at 24 h [64]. Mujalin Prasannarong et al. [65] found that
Ang-(1-7) could improve the inhibition of insulin signal transduction and glucose
transport activity caused by Ang II through the dependence of the Mas receptor, and
improve insulin resistance caused by RAS overactivity by enhancing the
phosphorylation of AKt.
3.3 ACE2/Ang-(1-7)/Mas axis and adipose tissue
Adipose tissue participates in glucolipid metabolism by secreting a series of
adipocytokines. Adiponectin (APN) produced by white adipose tissue is considered
to be a key regulator of insulin sensitivity and tissue inflammation, and its
expression is negatively correlated with body fat content [66, 67]. The fat
content was decreased, and APN levels were increased in TGR(A1-7)3292 rats, whose
level of Ang-(1-7) increased approximately 2-fold compared with control rats. The
increase in total AKt and phosphorylated AKt in adipose tissue suggests that the
PI3K/AKt pathway can be activated by chronically high levels of Ang-(1-7).
In vitro experiments showed that APN levels were up-regulated, and the
insulin-induced glucose uptake increased 2-fold after adipocytes were pretreated
with Ang-(1-7), which was blocked by A779 [36]. In rats given fructose, after
continuous infusion of Ang-(1-7), the phosphorylation of AKt and GSK-3
in the liver, skeletal muscle and adipose tissue was increased, and the insulin
resistance in the rats was significantly improved. This effect was blocked by
A-779, which confirmed that Ang-(1-7) could increase the activity of the PI3K/AKt
signal transduction pathway related to insulin metabolism in adipose tissue [68].
The adipose tissue of obese Zucker rats showed increased expression and release
of angiotensinogen (AGT) [69], which is considered to be an important feature of
preadipocyte differentiation [70]. The expression of AGT was significantly
increased in adipose tissue of Mas knock-out rats, suggesting that the
ACE2/Ang-(1-7)/Mas axis inhibited the expression of AGT in adipose tissue [71].
Studies showed that Mas-deficient mice had decreased insulin sensitivity,
impaired glucose tolerance (increased fasting blood glucose), and increased
insulin resistance. In adipose tissue, the expression of fat content was
increased, APN and GLUT4 was significantly down-regulated, and glucose uptake in
adipose tissue was decreased, which suggested that the ACE2/Ang-(1-7)/Mas pathway
plays an important role in insulin sensitivity [72]. Liu et al. [45]
reported that Ang-(1-7) can inhibit the expression of NAPDH oxidase mRNA in
adipose tissue, reduce the production of ROS, and increase insulin-stimulated
glucose uptake, thereby improving glucose metabolism. Ang-(1-7) may also decrease
obesity by stimulating brown adipose tissue [73].
3.4 ACE2/Ang-(1-7)/Mas axis and hepatic gluconeogenesis
There are few reports on the role of ACE2/Ang-(1-7)/Mas axis in liver glucose
metabolism. Bilman et al. [74] used SD rats and TGR(A1-7)3292 rat models
to observe changes in hepatic gluconeogenesis and glycogen synthesis. After
fasting overnight, the two groups of rats were treated with pyruvate. Compared
with SD rats, TGR (A1-7) 3292 rats had decreased gluconeogenesis and glycogen
synthesis. The main underlying mechanism may be as follows: high concentrations
of Ang-(1-7) down-regulate the transcription of hepatocyte nuclear factor
4, which down-regulates the expression of phosphoenolpyruvate
carboxykinase, which is the main rate-limiting enzyme of gluconeogenesis [74].
Recent studies have shown that Mas-deficient mice can lead to dysfunction of
hepatocyte mitochondria, increase fatty liver degeneration and gluconeogenesis,
and ultimately lead to apoptosis. The Ang-(1-7)/Mas axis can improve liver
mitochondrial energy utilization and glucolipid metabolism through the
IRS-1/Akt/AMPK pathway [75]. In addition, studies have found that the
ACE2/Ang-(1-7)/Mas axis is involved in inhibiting the glucose transport mediated
by sodium-dependent glucose transporter 1 in the jejunal enterocytes of type 1
diabetic rats, suggesting that the ACE2/Ang-(1-7)/Mas axis may take part in the
regulation of postprandial blood sugar [76]. These observations need to be
confirmed by further research.
4. The relationship between ACE2/Ang-(1-7)/Mas axis and ACE/Ang
II/AT axis
The ACE2/Ang-(1-7)/Mas and ACE/Ang II/AT axes can both act to regulate glucose
metabolism, and contribute to the development of the metabolic syndrome and
obesity [77, 78]. In the pancreas, Ang II causes islet cell dysfunction,
ACE2/Ang-(1-7) reduces the dedifferentiation of islet cells in high-fat
diet rats [58], and ACE2 promotes the secretion of insulin from islet cells. In
the liver, exercise helps the ACE2/Ang-(1-7)/Mas axis to inhibit the effects of
the ACE/Ang II/AT axis, reduce metabolic disorders and decrease the incidence of
nonalcoholic fatty liver disease [79]. Ang-(1-7) inhibits liver fat synthesis
[80], and ACE2/Ang-(1-7)/Mas axis reduces hepatic steatosis [81]. In skeletal
muscle, normal doses of Ang II results in skeletal muscle insulin resistance, but
high doses of Ang II decreases insulin resistance, which may be related to the
increased expression of ACE2 and Mas protein expression [82]. In addition, the
ACE2/Ang-(1-7)/Mas axis can reverse the adverse effects of the ACE/Ang II/AT axis
on bone metabolism, thereby improving bone metabolism [83]. The ACE/Ang II/AT
axis is associated with glucose metabolic disorders in adipose tissue, while the
ACE2/Ang-(1-7)/Mas axis can improve glucose metabolism [84].
The activity of ACE2 plays an important role in the balance of the two axes, not
only because it increases the level of Ang-(1-7), but more importantly, it
reduces the concentration of Ang II. Ang II is an active peptide in RAS, and is one
of the most potent vasoconstrictors [85]. Ang II acts through AT and AT
receptors [86], and phosphorylates the serine/threonine insulin receptor
substrate-1 (IRS-1)/insulin receptor substrate-2 (IRS-2) in the insulin
signaling pathway, which affects normal tyrosine phosphorylation. This negatively
regulates the signal transduction downstream of IRS-1/IRS-2 and alters glucose
metabolism [82, 87]. Ang II can also directly inhibit the phosphorylation of AKt
and prevent the transfer of the GLUT4 to the muscle cell membrane, leading to
insulin resistance [88, 89]. It also inhibits ligandin between IRS-1 and
phosphatidylinositol 3-kinase (PI3K), which reduces the cellular activity of PI3K
and affects the activity of Akt [90, 91]. The activity of phosphofructokinase-2
and glycogen synthase kinase is reduced, which ultimately decreases glycolysis
and glycogen synthesis, and reduces the use of glucose by peripheral tissues [92, 93]. In addition, Ang II also inhibits the activation of Ras protein, weakens the
insulin-mediated Ras/mitogen-activated protein kinase (MAPK) signal pathway,
reduces the production of GLUT4 through gene regulation, and reduces the uptake
of glucose in peripheral tissues, which increases insulin resistance (see Fig. 3)
[94, 95, 96]. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can also
be used to treat diabetes. Studies have shown that the mechanism of ACEi and ARBs
involved in regulating glucose metabolism is not only related to its reduction of
Ang II levels and inhibition of ATR activation, but also the increase of ACE2
expression and Ang-(1-7) levels [97, 98, 99].
Fig. 3.
Potential mechanisms of Ang II and Ang-(1-7) in regulating
glucose metabolism. Ang II, angiotensin II; Ang-(1-7), angiotensin-(1-7); ATR,
Ang II type 1 receptor; Mas, Mas receptor; IR, insulin receptor; NADPH,
nicotinamide adenine dinucleotide phosphate; MAPK, mitogen-activated protein
kinase; ROS, reactive oxygen species; PI3K, phosphatidylinositol 3-kinase; AKt,
protein kinase B; GLUT4, glucose transporter-4; GSK3, glycogen synthase kinase-3;
AS160, AKt substrate of 160 kDa; PIP5K, phosphatidylinositol 4-phosphate
5-kinase; PFKFB2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2.
5. Conclusions
The ACE2/Ang-(1-7)/Mas pathway is involved in promoting the proliferation of
pancreatic -cells and increasing insulin secretion and increases the
sensitivity of skeletal muscle and adipose tissue to insulin and reduces liver
gluconeogenesis, in order to improve insulin resistance. Further investigations
of the effects of Ang-(1-7) on the function of pancreatic islet cells and related
mechanisms will provide new therapeutic targets for protecting the function of
pancreatic cells.
Abbreviations
ACE, angiotensin-converting enzyme; ACEi, ACE inhibitors; AGT, angiotensinogen;
Ang, angiotensin; AKt, protein kinase B; APN, adiponectin; ARBs, angiotensin
receptor blockers; AS160, AKt substrate of 160 kDa; AT, Ang II type 1
receptors; AT, Ang II type 2 receptors; GLUT4, glucose transporter-4;
GSK-3, glycogen synthase kinase3; IR, insulin receptor; IRS,
insulin receptor substrate; MAPK, mitogen-activated protein kinase; MEF, myocyte
enhancer factor; NADPH, nicotinamide adenine dinucleotide phosphate; NEP, neutral
endopeptidase; NO, nitric oxide; NOS, nitric oxide synthase; Nrf2, nuclear factor
erythroid 2-related factor 2; PFKFB2,
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2; PI3K,
phosphatidylinositol 3-kinase; PIP5K, phosphatidylinositol 4-phosphate 5-kinase;
RAS, rennin-angiotensin system; ROS, reactive oxygen species.
Author contributions
SZ designed the study and wrote the manuscript draft; WS and PJ supervised the
project and generated the final version of the paper.
Ethics approval and consent to participate
Not applicable.
Acknowledgment
Thanks to all the peer reviewers for their opinions and suggestions.
Funding
This study was supported by the National Natural Science Foundation of China
(No. 81602846), the Taishan Scholar Project of Shandong Province (No.
tsqn201812159), and the Key Research and Development Program of Jining Science
and Technology (No. 2019SMNS012).
Conflict of interest
The authors declare no conflict of interest.