Invest Clin 63(4): 435 - 453, 2022 https://doi.org/10.54817/IC.v63n4a09
Corresponding author: Jesús A. Mosquera-Sulbarán. Instituto de Investigaciones Clínicas “Dr. Américo Negrette”,
Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela. E-mail: mosquera99ve@yahoo.com
Angiotensin II and human obesity.
A narrative review of the pathogenesis.
Jesús Mosquera-Sulbarán
1
, Elena Ryder
1
, Renata Vargas
1
and Adriana Pedreáñez
2
1
Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina,
Universidad del Zulia, Maracaibo, Venezuela.
2
Cátedra de Inmunología, Escuela de Bioanálisis, Facultad de Medicina, Universidad
del Zulia, Maracaibo, Venezuela.
Keywords: obesity; angiotensin II; co-morbidities; adipose tissue; inflammation.
Abstract. Angiotensin II (Ang II) is a hormone and the main effector of
the renin-angiotensin system (RAS). This peptide has crucial pathophysiologi-
cal effects on hypertension, cardiac hypertrophy, endothelial proliferation, in-
flammation and tissue remodelling through G protein-coupled receptors. The
pro-inflammatory role of Ang II has been reported in various inflammatory pro-
cesses. Obesity is linked to a chronic inflammatory process which in turn is the
cause of some of its morbidities. Ang II is related to the comorbidities related
to the comorbidities of obesity, which include alterations in the heart, kid-
ney, hypertension and coagulation. In this regard, activation of AT1 receptors
by Ang II can induce an inflammatory process mediated by the transcription
factor NF-kB, triggering inflammation in various systems that are related to
the comorbidities observed in obesity. The aim of this review was to highlight
the pro-inflammatory effects of Ang II and the alterations induced by this hor-
mone in various organs and systems in obesity. The search was done since 1990
through Medline, EMBASE and PubMed, using the keywords: angiotensin II; an-
giotensin II, obesity; angiotensin II, kidney, obesity; angiotensin II, coagulation,
obesity; angiotensin II, inflammation, obesity; angiotensin II, adipose tissue,
obesity; angiotensin II, hypertension, obesity; angiotensin II, insulin resistance,
obesity; angiotensin II, adiponectin, leptin, obesity; angiotensin II, COVID-19,
obesity. Angiotensin II through its interaction with its AT1 receptor, can induce
alterations in diverse systems that are related to the comorbidities observed in
obesity. Therapeutic strategies to decrease the production and action of Ang II
could improve the clinical conditions in individuals with obesity.
436 Mosquera-Sulbarán et al.
Investigación Clínica 63(4): 2022
Angiotensina II y obesidad humana. Revisión narrativa
de la patogénesis.
Invest Clin 2022; 63 (4): 435 – 453
Palabras clave: obesidad; angiotensina II; co-morbilidades; tejido adipose; inflamación.
Resumen. La angiotensina II (Ang II) es una hormona y el principal efector
del sistema renina-angiotensina (SRA). Este péptido tiene importantes efectos
fisiopatológicos en la hipertensión, la hipertrofia cardíaca, la proliferación endo-
telial, la inflamación y la remodelación tisular a través de receptores acoplados
a la proteína G. El papel pro-inflamatorio de la Ang II se ha reportado en diver-
sos procesos inflamatorios. La obesidad está ligada a un proceso inflamatorio
crónico que a su vez es causa de algunas de sus morbilidades. Se ha demostrado
que la Ang II está relacionada con las comorbilidades de la obesidad, que inclu-
yen alteraciones en el corazón, el riñón, la hipertensión y la coagulación. En
este sentido, la activación de los receptores AT1 por la Ang II puede inducir un
proceso inflamatorio mediado por el factor de transcripción NFkB desencadena-
do inflamación en diversos sistemas que se relacionan con las co-morbilidades
observadas en la obesidad. El propósito de esta revisión fue destacar el efecto
pro-inflamatorio de la Ang II y las alteraciones inducidas por esta hormona en
diversos órganos y sistemas en la obesidad. La búsqueda se hizo desde 1990 a
través de Medline, EMBASE and PubMed, utilizando las palabras clave: angioten-
sina II; angiotensina II, obesidad; angiotensina II, riñón, obesidad; angiotensina
II, coagulación, obesidad; angiotensina II, inflamación, obesidad; angiotensin II,
adipose tissue, obesidad; angiotensin II, hipertensión, obesidad; angiotensin II,
resistencia a la insulina, obesidad; angiotensin II, adiponectina, leptina, obesidad;
angiotensina II, COVID-19, obesidad. La angiotensina II a través de su interac-
ción con su receptor AT1 puede inducir alteraciones en diversos sistemas que
están relacionados con las comorbilidades observadas en la obesidad. Estrategias
terapeúticas para disminuir su producción y la acción de la AngII pudieran mejo-
rar las condiciones clínicas en individuos con obesidad.
Received: 02-04-2022 Accepted:17-06-2022
INTRODUCTION
Angiotensin II (Ang II) is a hormone de-
rived from the enzymatic digestion of Angio-
tensin I by the ACE-1 enzyme in the renin-
angiotensin system (RAS). In addition to its
vasopressor property, this hormone interacts
with its AT1 receptor inducing proinflamma-
tory effects through the NF-kB transcrip-
tion factor and producing gene activation
that transcribes proinflammatory proteins
and molecules involved in oxidative stress,
among others
1-6
. In this way, Ang II induces
several inflammatory processes. It has been
reported that obesity is highly involved in
chronic inflammation
7- 9
and that Ang II may
play an important role in that inflammation
1, 10-14
.
Obesity constitutes a public health
problem in view of the associated comorbidi-
ties. The comorbidities associated with obe-
sity reach practically all organ systems: type
2 diabetes mellitus, glucose intolerance,
Angiotensin II and obesity 437
Vol. 63(4): 435 - 453, 2022
dyslipidemia, hypertension, coronary and
peripheral arteriosclerosis and venous insuf-
ficiency are some of them. Many of these co-
morbidities are associated with the inflam-
matory process of obesity
15
. At the time of
the pandemic induced by SARS-CoV-2 (CO-
VID-19), obesity, being an inflammatory pro-
cess accompanied by several comorbidities,
represents a high risk factor for progression
to severe disease and death
16
. During COV-
ID-19 there is an increased pro-inflammato-
ry process mediated by Ang II involving high
production of cytokines (cytokine storm)
17
.
This inflammatory process in a patient with
obesity and comorbidities could further ex-
acerbate the already existing inflammation
in these patients and determine a severe evo-
lution. In this regard, Ang II has been impli-
cated in the inflammatory process of obesity
and its comorbidities
1-6
. Previous studies
have shown an increase of serum pro-inflam-
matory proteins and high expression of AT1
receptor on circulating leukocytes during
the onset of the inflammatory process in
obesity without co-morbidities
8
. This sug-
gests an initial susceptibility to the action of
Ang II in the obesity inflammatory process.
Therefore, this review aims to describe the
proinflammatory mechanism of Ang II and
the possible mechanisms by which Ang II is
involved in obesity.
Angiotensin II overview
Angiotensin II is an octapeptide that be-
longs to the renin–angiotensin system (RAS)
and is produced by cleavages of renin form-
ing Ang I that in turn is converted to Ang II
by angiotensin converting enzyme-1 (ACE 1).
This conversion to Ang II involves the RAS
pathway (angiotensin-converting enzyme:
ACE); however, the non- RAS pathway (Ca-
thepsin D, Cathepsin G) can also participate
in Ang II production. The angiotensinogen is
produced in the liver, while renin is produced
in the kidney and Ang II in the vascular tis-
sue
2
. ACE2 is another carboxypeptidase that
cleaves one amino acid from Ang II leading
to the production of the heptapeptide vaso-
dilatory Ang 1–7
3, 4
and the balance between
ACE1 and ACE2 is crucial for controlling Ang
II levels
18
. Levels of Ang II can also be regu-
lated by chymase expressed in several tissues
(chymase-dependent Ang II-generating sys-
tem)
19
. These enzymes represent an alterna-
tive pathway to ACE in cardiac, vascular, and
renal tissue
19, 20
. Other aminopeptidases can
cleave Ang II and generate Ang III (2–8) and
Ang IV (3–8). Angiotensin III has similar ef-
fects to Ang II, although with lower potency
(Fig. 1)
5,
21
. Angiotensin IV exerts a pro-
tective role by increasing blood flow in the
kidney
22
and brain
23
. The presence of RAS
components has been observed locally in
several organs including the heart
24
, kidney
25
, brain
26
, pancreas
27
, and adipose tissues
28
,
where they have different functions and can
operate independently. In addition, a func-
tional intracellular RAS has been identified
29, 30
. The presence of local and intracellular
RAS suggests autocrine and apocrine effects
of Ang II in different tissues including pro-
inflammatory, proliferative, and pro-fibrot-
ic activities. In this regard, Ang II induces
oxidative stress, apoptosis, cell growth, cell
migration and differentiation, extracellular
matrix remodeling, regulation of inflamma-
tory gene expression and can activate mul-
tiple intracellular signaling pathways leading
to tissue injury
14, 31
. According to this, the
mechanisms of Ang II action can be auto-
crine, paracrine, and endocrine.
Angiotensin II acts through two distinct
G protein-coupled receptors, angiotensin
type 1 (AT1, isoforms A and B) and the type
2 (AT2) receptors
6, 32
. AT1A confers actions
of Ang II such as blood pressure increase
33
,
salt retention in proximal tubular cells
34
, al-
dosterone release
35
, and stimulation of the
sympathetic nervous system in the brain
36
.
AT1B regulates blood pressure when AT1A
receptor is absent
37
. AT1 and AT2 recep-
tors have counter-regulatory actions in the
cardiovascular and renal system
38
. AT2 re-
ceptor induces vasodilation and improves
artery remodeling and it is upregulated dur-
ing cardiovascular injury
37
. Angiotensin II