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