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

, Elena Ryder

, Renata Vargas

and Adriana Pedreáñez

Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina,

Universidad del Zulia, Maracaibo, Venezuela.

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

. 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

. During COV-

ID-19 there is an increased pro-inflammato-

ry process mediated by Ang II involving high

production of cytokines (cytokine storm)

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

. 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

. 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

. Levels of Ang II can also be regu-

lated by chymase expressed in several tissues

(chymase-dependent Ang II-generating sys-

tem)

. 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)

. Angiotensin IV exerts a pro-

tective role by increasing blood flow in the

kidney

and brain

. The presence of RAS

components has been observed locally in

several organs including the heart

, kidney

, brain

, pancreas

, and adipose tissues

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

salt retention in proximal tubular cells

, al-

dosterone release

, and stimulation of the

sympathetic nervous system in the brain

AT1B regulates blood pressure when AT1A

receptor is absent

. AT1 and AT2 recep-

tors have counter-regulatory actions in the

cardiovascular and renal system

. AT2 re-

ceptor induces vasodilation and improves

artery remodeling and it is upregulated dur-

ing cardiovascular injury

. Angiotensin II

438 Mosquera-Sulbarán et al.

Investigación Clínica 63(4): 2022

also activates AT1 receptor to induce pro-

inflammatory, vasoconstriction, and fibrosis

effects; however, activation of AT2 receptor

to induce pro-inflammatory effect through

NF-kB pathway activation has been also re-

ported

38-40

. AT1 and AT2 receptors also bind

Ang III (2-8) and AT4 receptor binds Ang IV

(3-8)

Obesity and Inflammation

Obesity is associated with chronic in-

flammation that increases the risk of devel-

oping metabolic diseases, which include hy-

pertension, insulin resistance (IR), altered

glucose tolerance, hyperinsulinemia, and

dyslipidemia

; alterations that together

represent the metabolic syndrome (MS). In-

sulin resistance is a complication of chronic

inflammation associated to monocyte/mac-

rophage infiltration and activation of the

adipose tissue. This chronic inflammation

involves both innate and adaptive immune

system

7-10, 43-46

Angiotensin II (Ang II) has

been associated to obesity morbidities

10, 47

During obesity, the precursor of Ang II (an-

giotensinogen, produced in liver and adipose

tissue) is up regulated and related to the

growth of adipose tissue and the regulation

of blood pressure

. Thus, Ang II initiates

the activation of an inflammatory process

that includes increased oxidative stress, and

production of cytokines, chemokines, and

growth factors mediated by transcription

factor NF-κB activation

. In this way, Ang II

initiates a chain of inflammatory processes

that induce various co-morbidities observed

in obesity.

Angiotensin II and adipose tissue

The renin angiotensin system plays a

critical role in the pathogenesis of obesity,

obesity-associated hypertension, and IR

Angiotensin II can be produced by human

adipose tissue; in this regard, angiotensin-

ogen and the enzymes involved in its con-

version to Ang II, and both the RAS (renin,

Fig. 1. Renin angiotensin system. The angiotensinogen is transformed into Ang I by the action of the enzyme

renin. Ang I is transformed into Ang II by the action of ACE 1, cathepsins D and G or by chymase. In

addition to, Ang I can be converted into Ang 1-9 by ACE2 that under the action of ACE 1 converted

into Ang 1-7. Ang II can also be converted into Ang 1-7 by ACE2 which under the action of ACE 1 can

be transformed into Ang 1-5. Various aminopeptidases can act on Ang II to produce Ang 2-8 and Ang

3-8. ACE 1: angiotensin converting enzyme-1; ACE 2: angiotensin converting enzyme-2; DAP I-III:

Dipeptidyl-aminopeptidase I-III; APA: aminopeptidase A; APN: aminopeptidase N; Ang I: angiotensin-I;

Ang II: angiotensin-II; Ang 1-5: angiotensin-1-5; Ang 1-7: angiotensin-1-7; Ang 1-9: angiotensin-1-9;

Ang 2-8: angiotensin-2-8; Ang 3-8: angiotensin-3-8.

Angiotensin II and obesity 439

Vol. 63(4): 435 - 453, 2022

angiotensin-converting enzyme: ACE) and

non- RAS (cathepsin D, cathepsin G) path-

ways are expressed in human adipose tis-

sue. In addition, Ang II receptors are also

expressed in adipose tissue suggesting a lo-

cal role of this hormone in the regulation

of adipogenesis, lipid metabolism and in

the pathogenesis of obesity

28,

. The influ-

ence of Ang II on adipocytes is mediated by

АТ1 and АТ2 receptor activation, involving

different systems of signal transduction, in-

cluding Са 2+ responses, cell proliferation

and differentiation, accumulation of tri-

glyceride, adipokine gene expressions and

adipokine secretion

. Angiotensin II also

has anti-adipogenic effect by reducing dif-

ferentiation of human pre-adipose cells

Therefore, this hormone could be a protec-

tive factor against uncontrolled expansion

of adipose tissue

. This Ang II anti-adipo-

genic effect has also been observed in omen-

tal fat of humans with obesity, involving the

participation of the extracellular signal-reg-

ulated kinase/1,2 (ERK/1,2) pathway and

the phosphorylation of peroxisome prolifer-

ator-activated receptor gamma (pPARG)

52,

. During this process, the origin of Ang II

can be either by RAS or by non-RAS path-

ways, the latter may be more important in

this process

. However, in addition to this

effect, Ang II can increase triglyceride con-

tent and the activities of two lipogenic en-

zymes (FAS: fatty acid synthase, and GPDH:

glycerol-3-phosphate dehydrogenase) in

primary cultures of human adipose cells,

suggesting control of adiposity through

regulation of lipid synthesis and storage in

adipocytes

. Ang II also regulates the re-

gional blood flow to adipose tissue and the

size and number of fat cells

. These find-

ings have been confirmed by experimental

blocking of Ang II, which directly influences

body weight and adiposity (Fig. 2)

The autocrine regulation of Ang II dur-

ing adipogenesis has also been documented.

Angiotensin II can be catabolized in adipose

tissues by

adipose angiotensin-converting

enzyme 2 (ACE2) to form Ang 1-7. The au-

tocrine regulation of the local angiotensin

system implies co-expression of Ang II recep-

tors (AT1 and AT2) and Ang 1-7 receptors

(Mas) on adipocytes. Activation of the Mas

receptor by Ang 1-7 has an effect contrary

to the anti-adipogenic effect of Ang II by in-

ducing adipogenesis via activation of PI3K/

Akt and inhibition of MAPK kinase/ERK

pathways

In this context, the autocrine

regulation of the Ang II/AT1-ACE2-Ang 1-7/

Mas axis during adipogenesis is capable of

producing hormones and cytokines that pro-

mote inflammation, lipid accumulation, IR

and the components of the RAS, which are

activated in the presence of obesity as key

obesity-related mechanisms of hypertension

and other components of the cardiometabol-

ic syndrome (Fig. 2)

Angiotensin II as a pro-inflammatory

agent in obesity

Previous studies have demonstrated

the role of Ang II in the inflammation dur-

ing the obesity. Recently, several experimen-

tal studies have shown that Ang II mediates

important events of the inflammatory pro-

cesses

. Local activation of RAS and Ang

II synthesis increase vascular permeability,

mediated by the expression and secretion of

vascular endothelial growth factor (VEGF)

61-63

, and induce endothelial adhesion mole-

cules expression, such as P and L selectins,

vascular cell adhesion molecules-1 (VCAM-

1), intercellular adhesion molecules-1

(ICAM-1) and their ligands

64-66

, favoring the

recruitment of infiltrating inflammatory

cells into tissues. In addition, this effect is

enhanced by the production of specific cy-

tokine/ chemokines, also mediated by Ang

II/ AT1 receptor activation

67-69

. Angioten-

sin II also promotes endothelial dysfunction

through the cyclooxygenase 2 (COX-2) acti-

vation, which generates vasoactive prosta-

glandins and reactive oxygen species (ROS)

promoting mitochondrial dysfunction

70-72

In addition to those effects, a pro-fibrotic

effect of Ang II mediated by elaboration of

TGF-beta 1, a fibrogenic cytokine responsi-

440 Mosquera-Sulbarán et al.

Investigación Clínica 63(4): 2022

ble for connective tissue formation and tis-

sular deterioration has been reported

73, 74

Therefore, Ang II promotes inflammation

and tissue injury.

As above explained, Ang II has an im-

portant role in the accumulation of body fat

during obesity, and obesity is associated with

several medical conditions leading to death

. In this regard, obesity is associated with

the development of hypertension, type 2 dia-

betes, dyslipidemia, and cardiovascular and

renal diseases. Therefore, dysfunction of adi-

pose tissue has been proposed as the cause of

visceral obesity-related metabolic disorders,

leading to proinflammatory status

. In that

way, Ang II has been proposed as a promoter

of inflammation in obesity associated co-

morbidities (Fig. 3). Thus, both obesity and

hypertension have independently been asso-

ciated with increased levels of inflammatory

cytokines and immune cells within specific

tissues, mediated by increased activity of the

RAS

. Experimental studies have shown as-

sociation of obesity, Ang II and proinflamma-

tory processes. In this context, consumption

of a high-fat diet by mice induces proinflam-

Fig. 2. Adipogenic and anti-adipogenic effects of renin angiotensin system (RAS). Local production of Angio-

tensin II (Ang II) in adipose tissue, is involved in the regulation of adipogenesis and lipid metabolism.

Ang II has anti-adipogenic effect by reducing adipogenic differentiation of human pre-adipose cells

involving the participation of ERK(1,2) and the pPARG. Ang II can also increase triglyceride content

in adipocytes by activating two lipogenic enzymes, FAS and GPDH. This anti-adipogenic effect of Ang

II can be regulated. Ang II can be catabolized by adipose ACE2 to form Ang 1-7 which interacts with

Ang 1-7 receptors (Mas) on adipocytes, by activation of PI3K/Akt and inhibition of MAPK kinase/

ERK pathways and inducing inhibitory effect in the anti-adipogenic Ang II/AT1, promoting adipoge-

nesis. AT1: Angiotensin II receptor-1; AT2: Angiotensin II receptor-2; RAS: Renin Angiotensin System;

Cathep D, G: Cathepsin D, Cathepsin G; ACE1: angiotensin-converting enzyme-1; ACE2: angiotensin-

converting enzyme-2; Ang 1-7: Angiotensin 1-7; ERK(1,2): extracellular signal-regulated kinase(1,2);

pPARG: phosphorylated peroxisome proliferator-activated receptor gamma; FAS: fatty acid synthase;

GPDH: glycerol-3-phosphate dehydrogenase; MAPK kinase/ERK: mitogen-activated protein kinases

/ extracellular signal-regulated kinases; PI3K/Akt: phosphatidylinositol 3-kinase / protein kinase B.

Angiotensin II and obesity 441

Vol. 63(4): 435 - 453, 2022

matory responses in the hypothalamus and

the subfornical organ, which are known to

regulate blood pressure and energy balance

accompanied by increased RAS activity

The sensitization of Ang II-elicited hyperten-

sion by a high-fat diet in rats was reported,

mediated by upregulation of the brain RAS

and central proinflammatory cytokines

Exogenous administration of Ang II to rats

led to increased monocyte chemoattractant

protein-1 (MCP-1) expression in epididymal,

subcutaneous and mesenteric adipose tissue.

In vitro studies in Ang II treated adipocytes

showed increased MCP-1 production medi-

ated by AT1 receptor and NF-kB-dependent

pathway, suggesting a link between obesity,

Ang II and inflammation

. Angiotensin II

increases inflammation and endoplasmic re-

ticulum stress in adipocytes via AT1 receptor

and mediated by the miR-30 family, -708-5p

and/or -143-3p

. In a rat model of obesity

hypertension, induced by a high-fructose

diet, downregulation of adipose RAS, re-

duced inflammation in adipose tissue and

improved obesity hypertension

The initial factors involved in generat-

ing the inflammatory events in human obe-

sity remain unclear. Analysis regarding to

the presence of Ang II and its AT1 receptor

on individuals with obesity, without co-mor-

bidities, showed similar serum levels of Ang

II and decreased production of Ang II by cir-

culating mononuclear cells (CMC) in both,

individuals with obesity and controls. How-

ever, an increased number of CMC express-

ing the AT1 receptor was observed in indi-

viduals with obesity; suggesting that Ang II

production does not play an important role

in the early period of obesity inflammatory

alterations. However, high expression of Ang

II receptors may be a preliminary step, with

further cellular activation by Ang II

. These

findings may represent different functional

periods of Ang II in the obesity inflamma-

tory events to induce co-morbidities, in

which, the initial Ang II pro- inflammatory

effects are not found, but in advanced stag-

es of the obesity complications, this mole-

cule may have deleterious effects

. In this

regard, blocking of Ang II in overweight and

patients with obesity associated with mul-

tiple comorbidities results in a substantial

increase in adiponectin levels and improved

. Fig. 4 shows in a general way the in-

flammatory, vasopressor and insulin resis-

tance effects of Ang II.

Angiotensin II and kidney in obesity

Angiotensin II has been implicated in

renal damage during obesity. Obesity as

a proinflammatory state is associated to

kidney diseases and to the development

and progression of chronic kidney disease

(CKD). Angiotensin II plays an important

role in renal damage during obesity. In this

regard, increased Ang II contributes to hy-

perfiltration glomerulomegaly, by altering

renal hemodynamics, and subsequent focal

glomerulosclerosis

14, 31

. In addition, the im-

balance between increased Ang II and the

ACE2/Ang 1-7/Mas receptor axis, contrib-

utes additionally to renal injury in obesity.

Fig. 3. Pro-inflammatory effects of Angiotensin II (Ang II) on obesity. Ang II is intimately linked to obesity

and its pro-inflammatory effects are involved in their co-morbidities, such as insulin resistance, hype-

rinsulinemia, impaired glucose tolerance, dyslipidemia, and hypertension.

442 Mosquera-Sulbarán et al.

Investigación Clínica 63(4): 2022

The therapeutic blocking of the production

or action of Ang II improves the adverse ef-

fects on the kidney during obesity

. Angio-

tensin II regulates sodium/fluid homeostasis

and blood pressure in the kidney mediated

by the activation of AT1 receptors. In obesi-

ty, an exaggerated action of Ang II has been

implicated in the increased renal sodium

retention and the resetting of the pressure

natriuresis leading to hypertension. These

effects could be related to increased plasma

insulin levels observed in obesity which up-

regulate both AT1 and AT2 receptors in the

kidney

. During obesity and azotemia, the

oxidative stress stimulates synthesis of Ang

II, which in turn increases tumor growth

factor-beta (TGF-β) and plasminogen acti-

vator inhibitor-1 expressions, inducing glo-

merular fibrosis. Furthermore, in these pa-

tients, local synthesis of angiotensinogen by

Fig. 4 Interaction of Angiotensin II (Ang II) and its receptor (AT1R) during obesity. After activation of the

AT1receptor by Ang II, a series of intracellular processes are initiated that lead to increased blood

pressure, insulin resistance and production of co-morbidities during obesity. ROS: reactive oxygen

species; TNF: tumor necrosis factor; TF: tissue factor; Pal-1: plasminogen activator inhibitor-1; MCP-1:

monocyte chemoattractant protein1; TGF-beta: transforming growth factor-beta; NADPH: reduced

form of nicotinamide-adenine dinucleotide phosphate; IkB: inhibitor kB; NFkB: nuclear factor kB;

eNOS: endothelial nitric oxide synthase.

Angiotensin II and obesity 443

Vol. 63(4): 435 - 453, 2022

adipocytes, leptin activation of sympathetic

nervous system, and hyperinsulinemia con-

tribute to the development of hypertension

and CKD in obesity

. Renal abnormalities

induced by Ang II in the obesity may also be

related to the effects of oxidative stress on

the large conductance, Ca (2+)-activated K

(+) channels in podocytes. In addition, Ang

II induces podocyte apoptosis

. Other pos-

sible cause of renal failure is the excessive

leptin production in patients with obesity.

Leptin induces dysfunction of intrarenal ves-

sel endothelium and microalbuminuria and

increases circulating endothelin-1. These

disorders in obesity can be improved by ad-

ministration of Ang II receptor blockers

Experimental results show that obesity aug-

ments vasoconstrictor reactivity to Ang II

in the renal circulation of the Zucker rat,

providing insight into early changes in renal

function that predispose to nephropathy in

later stages of the disease

. Considering

the data exposed, Ang II has a relevant role

in the renal damage during obesity mediated

by structural, hemodynamic, and biochemi-

cal alterations (Fig. 5).

Angiotensin II and heart in obesity

Previous studies have reported that

during obesity, Ang II is able to induce car-

diac and arterial damage. Visceral adipose

tissue plays a key role in the metabolic and

cardiovascular complications in obesity. An-

giotensin II may be involved in modulating

both intracardiac lipid content and lipid

metabolism-related gene expression, in part

via AT1 receptor-dependent and pressor-in-

dependent mechanism

. Angiotensin II and

catecholamines may induce increased G pro-

tein-coupled receptor kinase 2 (GRK2) lev-

Fig. 5 Effects of Ang II on various organs and systems in obesity. Angiotensin II is involved in various effects

on the heart, kidney, insulin resistance, hypertension, coagulation, controlling leptin and adiponec-

tin levels, and inflammatory processes among others during obesity. Ang II: Angiotensin II; AT1:

Angiotensin II receptor-1; AT2: Angiotensin II receptor-2; RAS: Renin Angiotensin System; TGF-B:

Transforming growth factor-beta; ROS: Reactive oxygen species; AMPK: Adenine monophosphate -ac-

tivated protein kinase; PAL-1: plasminogen activator inhibitor-1; CKD: Chronic kidney disease; GRK2:

G protein-coupled receptor kinase 2; CNPS: cardiac natriuretic peptide system; ATRAP: AT1 receptor-

associated protein; TRPM2: Transient receptor potential melastatin 2.

444 Mosquera-Sulbarán et al.

Investigación Clínica 63(4): 2022

els in diverse cardiovascular cell types. This

can explain the contribution of increased

GRK2 levels to altered cardiovascular func-

tion and remodeling in obesity

. Lipid ac-

cumulation in the heart is associated with

obesity and may play an important role in

the pathogenesis of heart failure. Myocyte

steatosis can increase the fibrotic effects of

Ang II mediated by the activation of TGF-β

signaling and increased production of ROS

. The visceral adiposity and cardiometa-

bolic complications are linked to IR, sym-

pathetic nervous system, RAS and cardiac

natriuretic peptide system (CNPS). Renin

angiotensin system and CNPS are antagonis-

tic systems on sodium balance, cardiovascu-

lar system, and metabolism. As expressed,

RAS activity is increased in patients with

obesity; however, CNPS, which induces na-

triuresis and diuresis, reducing blood pres-

sure, and has powerful lipolytic activity is

found reduced in these patients. Thus, re-

duced CNPS effects coupled with increased

RAS activity have a central role in increased

obesity cardiovascular risk

. During obesity

increased serum Ang II and TNF-α levels have

also been reported. Experimental data have

shown that these two peptides may interact

to exacerbate myocardial ischemic/reperfu-

sion injury

. Atherosclerosis is a complex,

chronic disease that usually arises from the

converging action of several pathogenic pro-

cesses, including obesity, hypertension, hy-

perlipidemia, and IR. The capacity of Ang II

to induce atherosclerosis and cardiovascular

injury has been reported in both human and

animal studies

Despite the harmful Ang II

effects on the heart, some of its metabolites

(Ang 1-7) may have beneficial cardiovascular

and metabolic effects when Ang 1-7 inter-

acts with the Mas receptor (Fig. 5)

Angiotensin II and hypertension in obesity

Angiotensin II associated with obesity

represents a high risk factor of hypertension

in obese individuals. Angiotensin II is asso-

ciated with obesity hypertension

. Arterial

hypertension represents one of the comor-

bidities observed in obesity and the renin-

angiotensin-aldosterone system is an impor-

tant effector

. Obesity can increase the risk

of hypertension and cardiovascular disease

in individuals born prematurely, since obe-

sity may increase the prematurity-associated

imbalance in the RAS

. During obesity in-

creased levels of circulating leptin which can

increase sympathetic nerve activity and raise

blood pressure have been reported. This

leptin induced hypertension is mediated by

up-regulation of central RAS and proinflam-

matory cytokines

Angiotensin II is also capable of sup-

pressing AMPK activity in the kidney, leading

to sodium retention, enhanced salt-sensitiv-

ity, and hypertension

. In addition, obese

hypertensive men have a relative natriuretic

peptide deficiency and inadequate RAS sup-

pression, one of the mechanisms by which

obesity leads to hypertension

. Obesity and

vitamin D deficiency have both been linked

to augmented activity of the tissue RAS. In

obesity, decreased levels of 25-hydroxyvita-

min D are associated with increased vascular

sensitivity to Ang II leading to hypertension

(Fig. 5)

Angiotensin II and insulin resistance

in obesity

One of the obesity morbidities is the loss

of insulin sensitization of the insulin recep-

tor. Previous studies have demonstrated the

relationship of Ang II with insulin resistance.

Insulin is a hormone that allows glucose to

enter cells in different tissues which also

reduces blood glucose. Insulin resistance is

defined clinically as the inability of a known

quantity of exogenous or endogenous insu-

lin to increase cellular glucose uptake and

utilization in consequence blood glucose

levels increase. Obesity, sedentarism, and

family history of diabetes are some of risk

factors for IR

Previous studies have shown

that Ang II is an important promoter of IR

and diabetes mellitus type 2

100

. Angioten-

sin II-induced IR is suppressed by increased

AT1 receptor-associated protein (ATRAP) in

Angiotensin II and obesity 445

Vol. 63(4): 435 - 453, 2022

adipose tissue, hyperactivity of AT1 recep-

tor induced by Ang II decreases ATRAP and

could be related to IR

101

. Other mechanism,

as the action of redox-sensitive transient re-

ceptor potential melastatin 2 (TRPM2), has

been proposed. TRPM2 is a positive regula-

tor of Ang II-induced adipocyte IR via Ca

CaMKII/JNK-dependent signaling pathway.

Inhibition of TRPM2 improves insulin sensi-

tivity induced by Ang II in adipose tissue

102

Blocking of the AT-1 receptor also improves

IR mediated by Ang II and changes induced

by adiponectin in patients with diabetes

mellitus

103

. These data suggest that Ang II

increases the action of TRPM2 with subse-

quent IR production (Fig. 5).

Angiotensin II and adiponectin, and leptin

in obesity

Angiotensin II may modulate the ac-

tion of leptin and adiponectin in obesity.

There is evidence that dysregulation in the

production of adipocytokines is involved in

the development of obesity-related diseases.

Two important adipocytokines, leptin and

adiponectin are associated to obesity, IR, in-

creased risk of coronary heart disease and

type 2 diabetes mellitus. Decreased levels

of the anti-inflammatory adiponectin, while

increased levels of proinflammatory cyto-

kine leptin associated with obesity, IR and

endothelial dysfunction have been reported

104

. Leptin and adiponectin have opposite

effects on inflammation and IR. Leptin up-

regulates proinflammatory cytokines such

as TNF-α and interleukin-6 associated with

IR, type 2 diabetes mellitus and cardiovascu-

lar diseases in the obesity

104

. Angiotensin II

and its metabolites acting on AT1 receptor

can stimulate leptin production in human

adipocytes. This effect is mediated by an

extracellular-signal-regulated kinase 1 and

2-dependent pathway

105

and can increase

the pro-inflammatory activity of leptin dur-

ing obesity. On the other hand, leptin de-

creases Ang II-induced vascular effect by

blocking the vasoconstrictor action of Ang

II and inhibits the Ang II-induced increase

in intracellular Ca (2+) in vascular smooth

muscle cells

106

. Plasma concentrations of

adiponectin correlated negatively with a vast

majority of risk factors, such as obesity, type

2 diabetes, glucocorticoids, testosterone,

and hyperlipidemia, suggesting a protective

role of adiponectin. Blocking of RAS increas-

es plasma adiponectin suggesting a role of

Ang II in decreased levels of adiponectin.

Supporting this, Ang II infusion decreased

plasma adiponectin and adiponectin mRNA

in adipose tissue. Angiotensin II also inter-

acts with adiponectin in their target cells.

In this regard, the misbalance between adi-

ponectin, Ang II, and IR in endothelial cells

can determine the endothelial dysfunction in

metabolic syndrome and obesity

107-109

. There

is evidence indicating that adiponectin has

reno-protective effects and protects against

the development of albuminuria induced by

Ang II in obesity (Fig. 5)

110

, suggesting that

Ang II-decreased effect on adiponectin may

be involved in renal damage.

Angiotensin II and coagulation in obesity

Angiotensin II may alter the fibrinolytic

system in obesity. The connection between

obesity and hemostasis disorders is well es-

tablished. The inhibition of fibrinolysis in the

obesity, associated to increased plasma inhib-

itor, plasminogen activator inhibitor-1 (PAI-

1) has been documented

111, 112

. PAI-1 is the

main inhibitor of the fibrinolytic system and

was recently shown to be produced by adipose

cells. Obesity is associated with an increased

production and release of PAI-1 protein. An-

giotensin II and its metabolites promote PAI-

1 production and release by human fat cells

and may contribute to the impairment of the

fibrinolytic system typical for obesity. AT1 re-

ceptor blockade reduces basal and abolishes

Ang II-stimulated PAI-1 release from human

adipocytes (Fig. 5)

111, 112

CONCLUSION

The renin angiotensin system and espe-

cially Ang II are highly involved in the patho-

446 Mosquera-Sulbarán et al.

Investigación Clínica 63(4): 2022

logical events that occur in obesity. Angio-

tensin II through its interaction with its AT1

receptor can induce alterations in diverse

systems that are related to the comorbidi-

ties observed in obesity. Therapeutic strate-

gies to decrease the production and action

of Ang II could improve the clinical condi-

tions in individuals with obesity.

Limitations of the review

The reports studied for this review are

only based on the concept of obesity refer-

ring to individuals with a BMI greater than

30, with or without morbidities.

ACKNOWLEDGEMENTS

We thank Instituto de Investigaciones

Clínicas Dr. Américo Negrette, Facultad de

Medicina, Universidad de Zulia, Maracaibo,

Venezuela.

Funding

This manuscript has no financial sup-

port.

Declaration of conflict of interest

The authors have no competing inter-

ests to declare that are relevant to the con-

tent of this article.

ORCID Numbers

• Jesús Mosquera (JM-S):

0000-0002-1496-5511

• Elena Ryder (ER):

0000-0003-4613-6424

• Renata Vargas

• Adriana Pedreañez (AP):

0000-0002-3937-0469

Author’s contributions

JM-S and ER conceived the subject

matter and contributed to the design of the

work. JM-S, ER, RV and AP contributed to

the acquisition, analysis, or interpretation

of data for the work. JM-S and ER wrote the

original draft. JM-S, ER, RV and AP critically

revised the first draft. All authors approved

the final version for all aspects of work en-

suring integrity and accuracy.

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