Environmental Science and Pollution Research (2022) 29:62235–62247

https://doi.org/10.1007/s11356-021-16356-2

MUTAGENIC FACTORS IN THE ENVIRONMENT IMPACTING HUMAN AND ANIMAL HEALTH

Mechanical dependency of the SARS-CoV-2 virus

and the renin-angiotensin-aldosterone (RAAS) axis: a possible
new threat
Rohit Sen 1 & Devashish Sengupta 2 & Avinaba Mukherjee 1

Received: 16 April 2021 / Accepted: 1 September 2021 / Published online: 2 December 2021
# The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Pathogens in our environment can act as agents capable of inflicting severe human diseases. Among them, the SARS-CoV-2
virus has recently plagued the globe and paralyzed the functioning of ordinary human life. The virus enters the cell through the
angiotensin-converting enzyme-2 (ACE-2) receptor, an integral part of the renin-angiotensin system (RAAS). Reports on
hypertension and its relation to the modulation of the RAAS are generating interest in the scientific community. This short
review focuses on the SARS-CoV-2 infection’s direct and indirect effects on our body through modulation of the RAAS axis. A
patient having severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, which causes COVID-19 relates to
hypertension as a pre-existing disease or develops it in a post-COVID scenario. Several studies on how SARS-CoV-2 modulates
the RAAS axis indicate that it alters our body’s physiological balance. This review seeks to establish a hypothesis on the
mechanical dependency of SARS-CoV-2 and RAAS modulation in the human body. This study intends to impart ideas on drug
development and designing by targeting the modulation of the RAAS axis to inactivate the pathogenicity of the SARS-CoV-2
virus. A systematic hypothesis can severely attenuate the pathogenicity of the dreadful viruses of the future.

Keywords SARS-CoV-2 . Environmental pathogen . ACE2 receptor . RAAS system . Hypertension

Introduction Pathogens like SARS-CoV-2 lead to fatal outcomes, especially

in immunocompromised patients infected with the virus (Belsky
The outbreak of COVID-19 due to severe acute respiratory et al. 2021). Differences in mortality rates among different age
syndrome coronavirus-2 (SARS-CoV-2) has affected millions groups of the population can be linked with the differential status
of people globally, wherein about 3.5 million died due to this of the endocrine system, behavioral system, and physiological
outbreak (Dyer 2021; Woolf et al. 2021). However, recent conditions related to the age groups of the infected human pop-
data have suggested that the actual global mortality due to ulation (Undurraga et al. 2021). The pathogenicity of the coro-
COVID infection is almost 6.9 million (Dyer 2021). navirus is attributed to the high affinity of the spike protein that
binds with the angiotensin-converting enzyme (ACE)-2 recep-
tors, particularly in the lungs. It is known that ACE2 receptors
Responsible Editor: Lotfi Aleya
act as an integral part of an axis termed as the renin-angiotensin-
* Avinaba Mukherjee
aldosterone system (RAAS) (Lavoie and Sigmund 2003;
mukherjeeavinaba@gmail.com Tikellis and Thomas 2012). There is, therefore, a possibility
of modulation of such an essential endocrine axis after
Rohit Sen
robikolom1996@gmail.com COVID infection. Several studies have been made on
the impact of COVID on the RAAS axis. However,
Devashish Sengupta
the current data are scattered in a discrete pattern. In
devashish.sengupta@alumni.sydney.edu.au
this review, we attempt to summarize the effects of
1
Department of Zoology, Charuchandra College, University of SARS-CoV-2 on the RAAS axis. Also, we have linked
Calcutta, 22, Lake Road, Kolkata 700029, India the impact of SARS-CoV-2 on RAAS-mediated
2
Department of Chemistry, Assam University, Silchar, Assam 788 crosstalk signaling processes such as hypertension and
011, India behavioral alteration.
62236 Environ Sci Pollut Res (2022) 29:62235–62247

Effect of SARS-CoV-2 on angiotensin the other hand, angiotensin III is also called as Ang-(2-8).
Aminopeptidase A (APA) cleaves the Asp1-Arg2 bond in
The RAAS system has a crucial role in controlling the reten- Ang II and coverts it into Ang III. The major function of
tion of salts and water in the circulatory system via renal Ang III is to regulate hypertension and vasopressin release
reabsorption, thus regulating blood pressure (Vaduganathan (Reaux et al. 2001).
et al. 2020). Angiotensin, specifically Ang II, is the main AT2R is another important factor in RAAS regulation as both
contributor to the RAAS system by stimulating aldosterone angiotensin II and angiotensin III are modulated after SARS-
secretion, the main end product of the glomerulosa layer, in CoV-2 infection. Though AT2R has a significant role in the
the adrenal cortex. Membrane-bound aminopeptidase ACE2 vasodilation of vascular epithelium AT2R, it lacks any impact
is a regulatory enzyme that cleaves the active form of both in RAAS regulation while Na+ excretion through the kidneys
angiotensin I and angiotensin II into angiotensin 1–9 and an- increases (Sumners et al. 2015). Angiotensin III might positively
giotensin 1–7, respectively (Kuba et al. 2010; Strawn et al. affect Na+ reabsorption indirectly by interacting with AT2R in
1999; Ye et al. 2006). ACE2 maintains the physiological equi- the zona pellucida of the adrenals, but the concomitance of the
librium between the vasoconstrictor effect of angiotensin II vasodepressor is seen when synthetic {beta-Pro (7)} angiotensin
and thus of angiotensin 1–7, which lowers blood pressure by III is introduced (Del Borgo et al. 2015). It was earlier reported,
dilating the blood vessels (Fig. 1) (Burrell et al. 2004). due to virus infection, that ACE2 downregulation creates local
However, its infection by SARS-CoV-2 leads to the disrup- imbalance between the RAS and ACE2/angiotensin-(1–7)/MAS
tion of the homeostatic environment devised by RAAS. axis. This might directly lead to severe organ injury. Therefore,
Measuring blood levels of ACE2 after prospective validation the balance between angiotensin I and II, and 1–7 and 1–9, rather
is now known to provide a risk-stratification opportunity, than each one alone, may be the main determinant of dysfunc-
leading to the identification of individuals who are at greater tions related to the RAAS (Ni W et al. 2020). As a whole, SARS-
risk of infection or are susceptible to experiencing severe med- CoV-2infection-induced modulation in angiotensin and its relat-
ical complications. An opportunistic approach to protect ed receptor expression leads to several altered physiological con-
against the SARS-CoV-2 disease may be possible by targeting ditions in the human body.
the ACE2 system. For an individual patient, this may aid in
monitoring responses to preventive measures and treatment
interventions. Thus, focusing on the potential therapeutic Possible partial effect of SARS-CoV-2
strategy enabled by targeting ACE2 is especially important. on aldosterone
Autopsies of deceased COVID-19 patients show a remark-
able decrease in ACE2 expression (Oudit et al. 2009; SARS-CoV-2 infection upregulates angiotensin II after bind-
Chaudhry et al. 2020) along with severe lung injuries (He ing with the ACE2 receptor (Oudit et al. 2009; Chaudhry et al.
et al. 2006), due to inhibition of SARS-CoV-2. Further inves- 2020) as discussed earlier. On the other hand, angiotensin II
tigations show a correlation between elevated plasma angio- upregulates aldosterone secretion (Patel et al. 2017).
tensin II levels and lung injury along with viral load in severe- Therefore, after SARS-CoV-2 infection, there might be a pos-
ly infected patients (Liu et al. 2020; Miesbach 2020), indicat- sibility for the elevation of the aldosterone level. However, the
ing that ACE2 downregulation promotes angiotensin II. The reports supporting this are few, but some recent workers have
binding of angiotensin II with AT1 receptors can lead to en- found a positive correlation between upregulated aldosterone
hanced inflammation, vasoconstrictors, and thrombosis. On levels in COVID-19 patients’ bodies (Villard et al. 2020).

Fig. 1 Possible effect of RAAS

on blood pressure regulation.
Here, ACE2 means angiotensin-
converting enzyme 2, AT1R
means angiotensin type 1 receptor
and AT2R means angiotensin
type 2 receptor, AKKY C1 means
ankyrin C1 protein, CK1 means
casein kinase 1, and ENaC means
epithelial sodium channel
receptor
Environ Sci Pollut Res (2022) 29:62235–62247 62237

Mineralocorticoids provoke the epithelial sodium channel 2016; Soler et al. 2013; Kawabe et al. 2019) or facilitating the
(ENaC), also called amiloride-sensitive sodium channel, a conversion of angiotensin I to angiotensin II by cathepsins in
hetero-trimeric ion channel selectively permeable to sodium adipose tissue (Schütten et al. 2017). This deregulated renin/
ion targeting in the principal cell apical surface (Noreng et al. angiotensin/aldosterone axis that pre-exists in obese individ-
2018). Aldosterone facilitates ENaC function through media- uals may aggravate COVID-19. Meta-analytic data shows that
tor protein families of casein kinase (CK), ankyrin G the susceptibility to infection of COVID-19 increases a few
(Klemens et al. 2017), and even circadian rhythm controlling folds in obese individuals than in non-obese individuals, but
period 1 protein (Gumz et al. 2009). Casein kinase 1 delta/ also obesity aggravates the severity of the condition (Yang
epsilon, a subtype of CK protein, though the mechanism is et al. 2021; Hall et al. 2015; Zhang et al. 2021) along with it
still unclear, triggers ENaC-alpha expression (Yan et al. becoming a strong reason for comorbidities.
2007), i.e., it may act upon the transcriptional level of this On the other hand, obesity is strongly associated as a crit-
protein expression. In several studies, CK1 DELTA/ ical feature of diabetes in which high glucose levels induce the
EPSILON blockage checks ENaC mRNA expression by release of renin, as reported by Toma et al. (2008).
restricting PER-1 nuclear entry (Richards et al. 2012). Hyperactivation of the RAAS axis can therefore be observed
Therefore, a SARS-CoV-2-mediated disruption of the in diabetic patients (Ribeiro-Oliveira Jr et al. 2008).
RAAS system not only affects the respiratory and cardiovas- Hyperactivation of the RAAS axis could consequently help
cular systems but also might trigger the regulation of the cir- in the invasion of SARS-CoV-2. This observation is support-
cadian cycle. This behavioral alteration might be taken into ed by some recent data, which shows that diabetic patients are
consideration for COVID-19 patients due to elevated more prone to SARS-CoV-2 infectivity and mortality
aldosterone. (Feldman et al. 2020). Besides this, in diabetic patients, mono-
cyte and macrophage activation occur, which creates an ele-
vation of proinflammatory cytokines and chemokines like
Possible partial effect of SARS-CoV-2 on NO TNF α, IL6, IL8, and others (Kurihara et al. 2012). The
activity and hypertension heightened proinflammatory cytokines and chemokines create
inflammation in the body that might play a vital role in SARS-
Nitric oxide (NO) is a potent vasodilator; it inhibits the vaso- CoV-2 infection, especially in the generation of asymptomatic
constriction effects on blood vessels of angiotensin II disease (Xie et al. 2021).
(Richards et al. 2012). NO not only leads to the reduction of Among the renal abnormalities associated with COVID-19
blood pressure by inhibiting the AT1R in the vascular epithe- reports include proteinuria, hematuria, and acute kidney injury.
lium (Savoia et al. 2020) but also may drive angiotensin II and SARS-CoV-2 can infect podocytes, and tubular epithelial cells,
elevates the interaction of angiotensin II-AT2R. It facilitates contributing to the aforementioned renal abnormalities. The renal
the degree of lowering of blood pressure. If administered at abnormalities associated with COVID-19 are related to the rise in
the early stages of the infection, NO might play its role in the complex multifactorial pathophysiology involving the fol-
restricting the virus binding to the AT1R in the lungs by hin- lowing: (i) a local disruption in RAAS homeostasis, (ii) a direct
dering AT1R endocytosis of SARS-CoV-2 (Fig. 2). cytopathic effect of the virus, and a systemic inflammatory re-
sponse to infection (Martinez-Rojas et al. 2020). ACE2 supports
renal integrity and function through the enzymatic production of
Modulation of RAAS in other pathological angiotensin 1–7 (Ang1–7). Widely expressed ACE2 in proximal
conditions linked with SARS-CoV-2 infection epithelial cells, smooth muscle cells, vascular endothelial cells,
and podocytes acts as an anti-inflammatory, antifibrotic, vasodi-
RAAS is modulated not only in COVID-19 patients but also latory, and diuretic/natriuretic agent via activation of the
in several pathological conditions like obesity, diabetes, in- Mas receptor axis. Upon disruption of these activities in
flammations, renal disorders, and others, which might be the kidneys by ACE2, potential threats of renal damage
linked with accentuating the effects of SARS-CoV-2 infection leading to a high incidence of acute kidney injury
and creating comorbidities and asymptomatic disease in the (AKI) among SARS-CoV-2 patients are reported
human population. Obesity is yet another critical factor for (Armaly et al. 2021). The exogenous administration of
disrupting the RAAS axis and elevating the renin (Kalil and Ang (1–7) is considered an appealing therapeutic option,
Haynes 2012) and aldosterone secretion from the adrenal given the benefits of ACE2/Ang1–7, including attenua-
gland (Peminda et al. 2017; Yang et al. 2021). An adipokine tion of inflammation, vasodilation, diuresis, apoptosis,
named leptin upregulates renin via sympathetic activation natriuresis, oxidative stress, coagulation, and cell prolif-
through the CNS (brain stem and hypothalamus) (Peminda eration, as well as the high incidence of AKI in these
et al. 2017; Hall et al. 2010). Along with renin, angiotensin ACE2-depleted disorders (Martinez-Rojas et al. 2020;
II activity is enhanced either by inhibiting ACE2 (Patel et al. Armaly et al. 2021).
62238 Environ Sci Pollut Res (2022) 29:62235–62247

Fig. 2 Possible role of SARS-CoV-2 infection and alteration in the RAAS axis

Drugs that are capable of addressing obtained on humans show a contradiction of increased expres-
the alteration in the RAAS axis sion of the transmembrane ACE2 protein in the lung brought
about by anti-hypertension medications. Cardiovascular con-
Many drugs have been administered to block the RAAS axis. ditions can influence the expression of ACE2 in humans,
Some of these drugs are aldosterone receptor antagonist, which is independent of RAAS-blockade strategies of treat-
angiotensin-converting enzyme inhibitors (ACEi), sodium ment (Kai and Kai 2020; Gheblawi et al. 2020; Yehualashet
channel blocker, and potassium-sparing channel blocker, and Belachew 2020). A change in the use of angiotensin-
among others (Table 1). However, due to the COVID out- converting enzyme inhibitors (ACEIs) or angiotensin receptor
break, the main drug target area has also been modulated so blockers (ARBs) is not required to address the management of
that the pathogen can thrive in the human body and serve its elevated blood pressure in the treatment of COVID-19 infec-
detrimental effect by altering the RAAS axis. tion (Gressens et al. 2021). Though it is controversial whether
regular usage of these drugs affects ACE2 expression or not,
studies showed chronic hypertensive patients tend to have
Possible drug target area severe symptoms, and hypertension remained one of the main
factors for comorbidity (Clark et al. 2021). There is still no
Prompted by the fact that elderly patients with cardiovascular evidence for the involvement of elevated ACE2 in plasma
comorbidities have been gravely affected by the severe forms levels before infection due to the daily dosage of ARBs and
of SARS-CoV-2, interpretations based on retrospective obser- AREs (Ni et al. 2020). Studies show varied responses in pa-
vational studies about the influence of chronic treatment with tients to ACE2-modulating drugs. Thus, the therapeutic appli-
drugs that are blockers of RAAS are ongoing. However, these cation of such drugs also varied; most of them prescribed
retrospective interpretations should be published with caution persistence of medication. Alternative medication had been
and only evidence-based data on the impact of RAAS- devised in cases where AREIs and ARBs show adverse effects
interfering medications in patients and the general population (Jarari et al. 2016). Detailed studies on the impact of antihy-
should be published. Under in vivo conditions, reports on 15 pertensive drugs on ACE2 needed to be done, shedding light
classes of drugs in increasing ACE2 levels and a reanalysis of on the mechanisms and critical details affecting hypertension.
clinical data available from literature from a meta-analysis of 9 Since more severe hyper-mutative variants of the COVID-
studies have shown that an increased risk of mortality is not 19 virus are being identified, alternative approaches exploring
connected with the usage of ACEIs/ARBs (Akhtar et al. 2020; the modulation of the specific downstream pathophysiologic
Kai and Kai 2020; Yehualashet and Belachew 2020). Though effects caused by a virus that leads to morbidity and mortality
research on some animal sources implies enhancing ACE2 are being researched (Gressens et al. 2021). Opportunities to
expression or activity by drugs against hypertension, data understand the various aspects of RAAS inhibitors to alleviate
Environ Sci Pollut Res (2022) 29:62235–62247 62239

Table 1 List of RAAS inhibitors, their structures, and mechanism of action

Name of Inhibitors that act Structure of the drug Mechanism of
as drug Action
A. RAAS blocker/inhibitor
i. Direct Renin inhibitor Competitive renin
(e.g;Aliskiren) inhibitor which
binds to the active
site of the enzyme
(Wood 2003)

Molecular formula: C30H53N3O6

ii. Angiotensin-2 receptor It blocks the
blocker (ARB) Aldosterone receptor
and modulates its
activities.

a)Valsartan
Modulates the
mRNA expression
of ACE and AT1R
(Li et al. 2016)

Molecular Formula: C24H29N5O3

b) Irbesartan It selectively and
competitively blocks
the binding of
angiotensin II to the
angiotensin I
receptor.
Angiotensin II
stimulates
aldosterone
synthesis and
secretion by the
adrenal cortex,
which decreases the
excretion of sodium
and increases the
Molecular Formula: C25H28N6O excretion of
potassium.
Angiotensin II also
acts as a
vasoconstrictor in
vascular smooth
muscle (Hartner et
al. 2014).

c) Losartan Losartan and its

active metabolite
62240 Environ Sci Pollut Res (2022) 29:62235–62247

selectively and
competitively block
the binding of
angiotensin II to the
angiotensin I (AT1)
receptor. This blocks
the vasoconstrictive
and aldosterone-
secreting actions of
angiotensin II,
leading to a decrease
in blood pressure.
Angiotensin II,
Molecular Formula: C22H23ClN6O formed from
angiotensin I by
angiotensin-
converting enzyme
(ACE), stimulates
the adrenal cortex to
synthesize and
secrete aldosterone,
which decreases the
excretion of sodium
and increases the
excretion of
potassium.
Angiotensin II also
acts as a
vasoconstrictor in
vascular smooth
muscle
(Timmermans et al.
1995).
iii. Angiotensin Converting Blocks of activation
Enzyme Inhibitor (ACEi) of Angiotensin-
converting enzyme
and ANG 1-7 Mas
receptor.

a) Benazepril It competitively
binds to and inhibits
ACE, thereby
blocking the
conversion of
angiotensin I to
angiotensin II. This
prevents the potent
vasoconstrictive
actions of
angiotensin II
Environ Sci Pollut Res (2022) 29:62235–62247 62241

resulting in
vasodilation.
Benazeprilat also
decreases
angiotensin II-
induced aldosterone
secretion by the
adrenal cortex,
which leads to an
increase in sodium
excretion and
subsequently
Molecular Formula: C24H28N2O5 increases water
outflow (Liu et al
2011).

b) Lisinopril (dihydrate) Competitively

inhibits ACE, which
results in a decrease
in the production of
the potent
vasoconstrictor
angiotensin II and,
so, diminished
vasopressor activity.
In addition,
angiotensin II-
stimulated
aldosterone
secretion by the
adrenal cortex is
Molecular Formula: C21H35N3O7 decreased, which
results in a decrease
in sodium and water
retention and an
increase in serum
potassium (Iyer et
al. 1998).

c) Enalapril It competitively
binds to and inhibits
ACE, thereby
blocking the
conversion of
angiotensin I to
angiotensin II. This
prevents the potent
vasoconstrictive
actions of
angiotensin II and
62242 Environ Sci Pollut Res (2022) 29:62235–62247

results in
vasodilation.
Enalapril also
decreases
angiotensin II-
induced aldosterone
secretion by the
adrenal cortex,
which leads to an
increase in sodium
excretion and
subsequently
increases water
Molecular Formula:C20H28N2O5
outflow (Hair et al.
2007).

B Epithelial Na+ Channel (ENaC) Blocker.

a) Amiloride Directly blocks
Epithelial sodium
channels (Kleyman
1988, Vandenbeuch
2020).

Molecular Formula:C6H8ClN7O

C. K+ sparring diuretics
a) Spironolactone Competitively
blocks the
aldosterone
receptors (Layton
2017).

MolecularFormula:C24H32O4S
Environ Sci Pollut Res (2022) 29:62235–62247 62243

indirect viral-induced lung and other organ injuries are getting Internalization of ACE2 by SARS-CoV-2 upon entry into
attention (Ingraham et al. 2020). Patients with cardiovascular the target cell likely reduces cell-surface ACE2 levels, thus
comorbidities are often administered RAAS blockers. The translating into (i) the downregulation of Ang-(1–7), (ii) caus-
degree of ACE2 expression in different age groups combating ing unopposed Ang II accumulation, and (iii) RAAS activa-
severe infection of the virus and mortality is being hinted at tion promotion (Kaseb et al. 2021). ACE inhibitors and Ang
being directly related to the incidence and severity of COVID- II-receptor blockers as RAAS inhibitors serve as potential
19 virulence. The benefits or risks of pharmacologic modifi- therapeutic strategies to prevent SARS-CoV-2 infection.
cation of the RAAS-SCoV-axis by drugs that are possible Other options include modifying ACE2 levels or activity in
angiotensin-converting enzyme inhibitors (ACEIs) or angio- the target cells. As such, the therapeutic approaches for
tensin receptor blockers (ARBs) are still not very clear achieving the mentioned options are achievable by blocking
(Gressens et al. 2021). The possibility that these drugs may spike-protein priming by employing TMPRSS2 inhibitors,
facilitate viral cell entry has fueled controversies since the slowing the viral entry into target cells by using soluble re-
expression of ACE2 may be increased by RAAS blockers, combinant ACE2 to competitively bind with the COVID-19
yet by degrading angiotensin II into angiotensin, ACE2 func- virus serving as a virus trap and inactivator, and developing a
tions as a counter-regulator of the RAAS (Gressens et al. vaccine targeting the spike protein of SARS-CoV-2 (Kaseb
2021). While the former has led to concerns that such modu- et al. 2021; Ferrario et al. 2005; Akhtar et al. 2020).
lations may aggravate and worsen the condition of the pa- ACE2 is a membrane-bound aminopeptidase. The compo-
tients, the latter may mediate beneficial effects in COVID- sition of ACE2 is attributed to a carboxymonopeptidase that
19. The contemporary experimental models through relevant prefers hydrolysis between proline and carboxy-terminal hy-
preclinical approaches favor a protective outcome of RAAS- drophobic residues that is found both as a membrane-
CoV-axis inhibition on both lung injury and survival. But associated and as a secreted enzyme in cardiovascular, neuro-
there are limitations in clinical data related to the role of nal, and reproductive organs (Ferrario et al. 2005). Angiotensin
RAAS modulation in the setting of SARS-CoV-2. A clinical I and angiotensin II are cleaved into the angiotensin-(1–9) and
equipoise regarding the efficacy of RAAS-based interventions angiotensin-(1–7) peptides by ACE2 (Mourad and Levy 2020).
and the imminent need for a multisite randomized controlled ACE2 is overexpressed in heart failure, arterial hypertension,
clinical trial to evaluate the inhibition of the RAAS-SARS- and diabetes mellitus. The existence of a cardiovascular-
CoV-2 axis on acute lung injury in COVID-19 has been pro- protective ACE2–angiotensin-(1–7)–Mas receptor axis is sup-
posed (Ingraham et al. 2020). Based on viral microbiology, ported in several studies (Ferrario et al. 2005). Activation of
the target of the various proposed interventions for SARS- ACE2 is known to modulate the host and support its replica-
CoV-2 and the inhibition of viral cellular injury have been tion. Investigations about the role of ACE2 in activating the
proposed (Ingraham et al. 2020). immune signals on SARS-CoV-2 attachments have prompted
There is evidence that there may be a relation between the construction of the host regulatory network upon the viral
ACE2 and the differences in incidence and severity of attachment to the ACE2 receptor, specifically in the lungs (Lite
COVID-19 infection (Kaseb et al. 2021). The prevalence et al. 2021). The gene-expression profile of the human lung
and severity of COVID-19 among the vulnerable groups of was integrated with the host regulatory network to investigate
patients having age-related comorbidities with established the altered host signaling mechanism prevalent in the SARS-
high levels of ACE2 expression establish its candidacy as a CoV-2 viral infection. The immune modulation in the con-
potential therapeutic target. Evidence supports the idea that structed network, comprising 133 host proteins with 298 inter-
differences in the incidence and severity of COVID-19 infec- actions that directly or indirectly connect to the ACE2 receptor,
tion may be related to ACE2 (Kaseb et al. 2021). The preva- was also determined by functionally enriching the network.
lence and severity of SARS-CoV-2 among age- or gender-, or Results show that upon infection by SARS-CoV-2, the host
ethnicity-related comorbidity, with established high levels of lungs differentially regulated 29 proteins out of the 133 host
ACE2 expression, strongly support this inference. The burden proteins. The generation of a new network of the altered pro-
of COVID-19 infection in these vulnerable groups added to teins by connecting with multiple proteins was observed to
the impact of the potential therapeutic and preventive mea- modulate kinase, cytokine, and carboxypeptidase activity.
sures as a result of adopting ACE2-driven anti-viral strategies; This modulation leads to changes in the host immune system,
the expedition of a global approach to control the severe in- signal transduction mechanism, and cell cycle. Secondary
fection and mortality of the COVID-19 pandemic may be health complications were apparent from an investigation indi-
possible (Kaseb et al. 2021). Though in-depth clinical and cating similar signaling events in the kidneys, pancreas, small
mechanistic investigations are still ongoing, literature is indic- intestine, testes, placenta, and adrenal glands (Lite et al. 2021).
ative of the safety in the usage of ACEIs/ARBs, though, in The interconnected protein hubs are assumed to be activated
severe COVID-19 patients, there may be an increased risk of when the SARS-CoV-2 virus binds with the ACE2 receptor.
renal injury (Akhtar et al. 2020). The direct mediators of these protein hubs were AGT
62244 Environ Sci Pollut Res (2022) 29:62235–62247

(Angiotensinogen), LAMAS (Laminin Subunit Alpha 1), NTS reinfection with SARS-CoV-2 is poorly understood.
(Neurotensin), GHRL Ghrelin, and (ObestatinPrepropeptide) However, some recent works have found two distinct signif-
as revealed by the Interactome data. The association of a regu- icant genetic variants of SARS-CoV-2 infection in the same
latory network with various biological pathways responsible individual and were reported to be a case of reinfection of
for the disease, immune system, DNA repair, cell cycle, au- SARS-CoV-2 (Tillett et al. 2020). But as such, the possibility
tophagy, programmed cell death, transcription, and signal of reinfection with SARS-CoV-2 is not well understood.
transduction was revealed by the Reactome database (Lite Apart from vaccines, alternative medicines are available, and
et al. 2021). The presence of ACE2-inducible immune factors new medication with low side effects and preventive organ
across different tissue types was found to be very profound in effects in this extraordinary situation may find a possible way
the lungs compared to other tissues, thus making it more sen- out.
sitive. The overactive immune response leading to respiratory
illness could be an underlying molecular factor (Lite et al.
2021). Conclusion
ACE2 modulator drugs such as angiotensin-converting en-
zyme inhibitor (ACEi) though having a suppressing effect on This review highlights how SARS-CoV-2 infection in syner-
ACE2-induced hypertension and being reported to decrease gy with the RAAS axis can inflict the modulation of the
mortality (Chu et al. 2021) but less likely to be used in patients RAAS axis. Furthermore, this complex loop interdependence
with a prior chronic medical condition (like hypertension, di- between RAAS and SARS-CoV-2 gets more complicated as
abetes mellitus, cardiovascular disease) may show unlike ef- apparent in several pathophysiological conditions like diabe-
fects (Fang et al. 2020). In contrast to Na+ absorption, K+ tes; RAAS axis modulated by immunosuppressive conditions
secretion occurs through the cells of the epithelial lining of may accelerate the infectivity of SARS-CoV-2 because these
the renal tubule, but in COVID-19, uncontrolled K+ secretion diseases are known to raise the comorbidity. Overall, the pres-
may induce a hypokalemic condition in infected individuals ent review implies how COVID patients bear the alteration in
(Moreno-P et al. 2020) leading to the requirement of ventila- their RAAS axis and, therefore, changes in the physiological
tion support required by severely infected patients. But a high and behavioral aspects are brought about. Chronic hyperten-
K+ concentration in the blood has an inhibitory role in the sive individuals can be more susceptible to recurrence of the
RAAS system (Poulsen and Fenton 2019); thus, K+-sparing disease than the normal ones (Clark et al. 2021). Reinfection
drugs such as spironolactone is prescribed in few cases as an might be another problem that may arise in the future with a
alternative way of combating SARS-CoV-2 by bypassing the different and possibly more lethal strain of the SARS-CoV-2
adverse effects of ARBs and ACE (Cadegiani et al. 2020). virus.
In another article (Gumashta and Gumashta 2020), it is The development of new target-specific drugs against hy-
suggested that AT2R agonists might be a way to reduce the pertension, i.e., less dependent on ACE2, is vital. Other than
severity of the patients. Thus, it is well implicated that the that, modifying ACE2 levels or activity in the target cells is
ANG III/AT2R might be a new axis to be considered in drug highly solicited. Though this review ceases to show any re-
designing. ports of hypertension in COVID-19 survivors, active involve-
The aforementioned K+-sparing diuretics do not only in- ment of RAAS might be a possibility in triggering hyperten-
crease K+ reabsorption (Cadegiani et al. 2020) but may also sion in high-risk groups of the population. Infected patients
increase Na+ secretion by blocking the ENaCs (Fang et al. may bear the alteration in blood pressure and hypertension
2020). Amiloride, a potent potassium-sparing diuretic, has state through CoV-2-mediated RAAS alteration; therefore, it
multivariate potential as it not only suppresses the ENaC ac- is imperative to develop a conjugated approach to directional
tivity (Bhagatwala et al. 2014) but also has a direct effect in and hypertension therapy in a synergistic approach. Several
reducing blood pressure,cardiovascular risks, and often edema reports established that hypertension and the RAAS axis bear
observed during COVID infection (Hinrichs et al. 2018). the potential role in the pathogenicity of SARS-CoV-2 infec-
Since aldosterone blockers might hamper the activity of tion (Mancia et al. 2020; Jarari et al. 2016). Also, several
ACE2 (Fang et al. 2020), ENaC-blocking drugs might be studies and trials are underway on how the RAAS inhibitors
another bypass to adverse coronary effects. Research on could modulate the infectivity of SARS-CoV-2 (Zhang et al.
SARS-CoV-2 survivors with chronic hypertension and with- 2020; Vaduganathan et al. 2020).
out any hypertension is yet to be done, though ACE2 modu- The identification and characterization of the specific drug
lation may affect them in the future. target area and mechanism against SARS-CoV-2 remain an
Despite such a lack of knowledge of the risk of recurrence enigma to us, as is the role of antihypertensive drugs such as
of Covid-19, long-term effects of medication and weakened AREi and ARBs. Besides this, the possible mechanism behind
immunity may trigger the infection again. However, reinfec- the ACE2 modulator drugs or drug-induced modulation in K+
tion of SARS-CoV-2 is still unknown. Also, the possibility of and how they are involved in the possible lowering of the
Environ Sci Pollut Res (2022) 29:62235–62247 62245

SARS-CoV-2 infection is still an area that requires clarity. inhibition by amiloride on blood pressure and cardiovascular disease
risk in young pre hypertensives. J Clin Hypertens 16:47–53. https://
Along with the infection of SARS-CoV-2, simultaneous mod-
doi.org/10.1111/jch.12218
ulation of the RAAS axis occurs as it targets the ACE2 recep- Burrell LM, Johnston CI, Tikellis C, Cooper ME (2004) ACE2, a new
tor, which in turn remains an integral part of the RAAS axis. regulator of the renin-angiotensin system. Trends Endocrinol Metab
While the COVID-19 virus manifestations persist, there is a 15(4):166–169. https://doi.org/10.1016/j.tem.2004.03.001
Cadegiani FA, Goren A, Wambier CG (2020) Spironolactone may pro-
modulated RAAS axis posing immediate or post-COVID-19
tect SARS-CoV-2: targeting androgens, angiotensin-converting en-
threats for a prolonged time. This observation has not been zyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS).
focused upon and needs in-depth investigation or otherwise Med Hypotheses 143:110112. https://doi.org/10.1016/j.mehy.2020.
may culminate into neglect of significance. 110112
Chaudhry F, Lavandero S, Xie X, Sabharwal B, Zheng YY (2020)
Possibly, along with the therapy against SARS-CoV-2, re-
Manipulation of ACE2 expression in COVID-19. Open Heart
searchers must strategize solutions to the alteration in the RAAS 7(2):e001424. https://doi.org/10.1136/openhrt-2020-001424
axis simultaneously by providing an array of opportunities to Chu C, Zeng S, Hasan AA, Hocher CF, Krämer BK, Hocher B (2021)
reduce the severity and comorbidity in COVID-19 patients Comparison of infection risks and clinical outcomes in patients with
and without SARS-CoV-2 lung infection under renin–angiotensin–
achieved through the designing of competent drugs. At this
aldosterone system blockade: systematic review and meta-analysis.
point, the possible drug target area against SARS-CoV-2 is still Br J Clin Pharmacol 87:2475–2492. https://doi.org/10.1111/bcp.
unclear to us. The same is true about the role of antihypertensive 14660
medications such as AREi and ARBs. The possible mechanism Clark CE, McDonagh STJ, McManus RJ, Martin U (2021)COVID-19
of ACE2 modulator drugs or drug-induced modulation in K+ and hypertension: risks and management. A scientific statement on
behalf of the British and Irish Hypertension Society. J Hum
and how they are involved in lowering the SARS-CoV-2 infec- Hypertens 35:304–307. https://doi.org/10.1038/s41371-020-
tivity is still an area under investigation. 00451-x
Del Borgo M, Wang Y, Bosnyak S, Khan M, Walters P, Spizzo I,
Perlmutter P, Hilliard L, Denton K, Aguilar MI, Widdop RE,
Data and materials availability Yes Jones ES (2015)β-Pro7Ang III is a novel highly selective angioten-
sin II type 2 receptor (AT2R) agonist, which acts as a vasodepressor
agent via the AT2R in conscious spontaneously hypertensive rats.
Author contribution Mr. Rohit Sen designed the framework of the re- Clin Sci 129:505–513. https://doi.org/10.1042/CS20150077
view article and prepared the manuscript. Dr. Devashish Sengupta pro- Dyer O (2021) Covid-19: Study claims real global deaths are twice offi-
vided inputs about the biochemical and drug-related aspects of the re- cial figures. BMJ 373:n1188. https://doi.org/10.1136/bmj.n.1188
view. Dr. Avinaba Mukherjee supervised the entire manuscript prepara- Fang L, Karakiulakis G, Roth M (2020) Are patients with hypertension
tion and hypothesized the possible drug target area. and diabetes mellitus at increased risk for COVID-19 infection?
Lancet Respir Med 8:e21. https://doi.org/10.1016/S2213-2600(20)
Declarations 30116-8
Feldman EL, Savelieff MG, Hayek SS, Pennathur S, Kretzler M, Pop-
Ethics approval Not applicable Busui R (2020)COVID-19 and diabetes: a collision and collusion of
two diseases. Diabetes 69:2549–2565
Ferrario CM, Jessup J, Chappell MC (2005) Effect of angiotensin-
Consent to participate Yes converting enzyme inhibition and angiotensin II receptor blockers
on cardiac angiotensin-converting enzyme2. Circulation 111(20):
Consent for publication Yes 2605–2610. https://doi.org/10.1161/circulationaha.104.510461
Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ,
Competing interests None to declare. Raizada MK, Grant MB, Oudit GY (2020) Circ Res 126:1457–
1475. https://doi.org/10.1161/circresaha.120.317015
Gressens SB, Leftheriotis G, Dussaule JC, Flamant M, Levy BI, Vidal-
Petiot E (2021) Controversial roles of the renin angiotensin system
and its modulators during the COVID-19 pandemic. Front Physiol
References 12:624052. https://doi.org/10.3389/fphys.2021.624052
Gumashta J, Gumashta R (2020) Role of the backbenchers of the renin-
Akhtar S, Benter IF, Danjuma MI, Doi SAR, Hasan SS, Habib AM angiotensin system ACE2 and AT2 receptors in COVID-19: lessons
(2020) Pharmacotherapy in COVID-19 patients: a review of from SARS. Cureus 12(6):e8411. https://doi.org/10.7759/cureus.
ACE2-raising drugs and their clinical safety. J Drug Target 28:7– 8411
8. https://doi.org/10.1080/1061186x.2020.1797754 Gumz ML, Stow LR, Lynch IJ, Greenlee MM, Rudin A, Cain BD,
Armaly Z, Kinaneh S, Skorecki K (2021) Renal manifestations of Covid- Weaver DR, Wingo CS (2009) The circadian clock protein Period
19: physiology and pathophysiology. J Clin Med 10:1–21. https:// 1 regulates the expression of the renal epithelial sodium channel in
doi.org/10.3390/jcm10061216 mice. J ClinInvest 119(8):2423–2434. https://doi.org/10.1172/
Belsky JA, Tullius BP, Lamb MG, Sayegh R, Stanek JR, Auletta JJ JCI36908
(2021) COVID-19 in immunocompromised patients: a systematic Hair PI, Scott LJ, Perry CM (2007) Fixed-dose combination
review of cancer, hematopoietic cell and solid organ transplant pa- lercanidipine/enalapril. Drugs 67(1):95–106. https://doi.org/10.
tients. J Infect 82:329–338. https://doi.org/10.1016/j.jinf.2021.01. 2165/00003495-200767010-00007
022 Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy S,
Bhagatwala J, Harris RA, Parikh SJ, Zhu H, Huang Y, Kotak I, Seigler N, Smith G, Stec DE (2010) Obesity-induced hypertension: role of
Pierce GL, Egan BM, Dong Y (2014) Epithelial sodium channel sympathetic nervous system, leptin, and melanocortins. J Biol
62246 Environ Sci Pollut Res (2022) 29:62235–62247

Chem 285(23):17271–17276. https://doi.org/10.1074/jbc.R110. retinal neural dysfunction. Int J Inflamm 2012:581695. https://doi.
113175 org/10.1155/2012/581695
Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME (2015) Obesity- Lavoie JL, Sigmund CD (2003) Minireview: Overview of the renin-
induced hypertension: interaction of neurohumoral and renal mech- angiotensin system— an endocrine and paracrine system.
anisms. Circ Res 116:991–1006. https://doi.org/10.1161/circresaha. Endocrinology 144:2179–2183. https://doi.org/10.1210/en.2003-0150
116.305697 Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van
Hartner A, Cordasic N, Klanke B (2014) Renal protection by low dose Zuuren EJ (2017) Oral spironolactone for acne vulgaris in adult
irbesartan in diabetic nephropathy is paralleled by a reduction of females: a hybrid systematic review. Am J Clin Dermatol 18:169–
inflammation, not of endoplasmic reticulum stress. Biochim 191. https://doi.org/10.1007/s40257-016-0245-x
Biophys Acta 1842:558–565. https://doi.org/10.1016/j.bbadis. Li Y, Cai S, Wang Q, Zhou J, Hou B, Yu H, Ge Z, Guan R, LiuX (2016)
2014.01.001 Valsartan attenuates intimal hyperplasia inballoon-injured rat aortic
He L, Ding Y, Zhang Q, Che X, He Y, Shen H, Wang H, Li Z, Zhao L, arteries through modulating theangiotensin-converting enzyme 2-
Geng J, Deng Y, Yang L, Li J, Cai J, Qiu L, Wen K, Xu X, Jiang S angiotensin-(1-7)-Masreceptor axis. Arch Biochem Biophys 598:
(2006) Expression of elevated levels of pro-inflammatory cytokines 11–17. https://doi.org/10.1016/j.abb.2016.03.028
in SARS-CoV-infected ACE2+ cells in SARS patients: relation to Lite C, Ahmed SSSJ, Juliet M, Freddy AJ (2021) SARS-CoV-2/human
the acute lung injury and pathogenesis of SARS. J Pathol 210(3): interactome reveals ACE2 locus crosstalk with the immune regula-
288–297. https://doi.org/10.1002/path.2067 tory network in the host. Pathog Dis 79:1–9. https://doi.org/10.1093/
Hinrichs GR, Mortensen LA, Jensen BL, Bistrup C (2018) Amiloride femspd/ftab005
resolves resistant edema and hypertension in a patient with nephrotic Liu CX, Hu Q, Wang Y, Zhang W, Ma ZY, Feng JB, Wang R, Wang XP,
syndrome; a case report. Phys Rep 6:e13743. https://doi.org/10. Dong B, Gao F, Zhang MX, Zhang Y (2011) Angiotensin-
14814/phy2.13743 converting enzyme (ACE) 2 overexpression ameliorates glomerular
Ingraham NE, Barakat AG, Reilkoff R, Bezdicek T, Schacker T, injury in a rat model of diabetic nephropathy: a comparison with
Chipman JG, Tignanelli CJ, Puskarich MA (2020) Understanding ACE inhibition. Mol Med 17:59–69. https://doi.org/10.2119/
the renin–angiotensin– aldosterone–SARS-CoV axis: a comprehen- molmed.2010.00111
sive review. Eur Respir J 56:2000912. https://doi.org/10.1183/ Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, Li J, Li J,
13993003.00912-2020 Feng C, Zhang Z, Wang L, Peng L, Chen L, Qin Y, Zhao D, Tan S,
Iyer SN, Chappell MC, Averill DB, Diz DI, Ferrari CM (1998) Yin L, Xu J et al (2020) Clinical and biochemical indexes from
Vasodepressor actions of angiotensin-(1–7) unmasked during com- 2019-nCoV infected patients linked to viral loads and lung injury.
bined treatment with lisinopril and losartan. Hypertension 31:699– Sci China Life Sci 63:364–374. https://doi.org/10.1007/s11427-
705. https://doi.org/10.1161/01.HYP.31.2.699 020-1643-8
Jarari N, Rao N, Peela JR, Ellafi KA, Shakila S, Said AR, Nelapalli NK, Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G (2020) Renin–
Min Y, Tun KD, Jamallulail SI, Rawal AK, Ramanujam R, Yedla angiotensin–aldosterone system blockers and the risk of Covid-19.
RN, Kandregula DK, Argi A, Peela LT (2016) A review on pre- N Engl J Med 382:2431–2440. https://doi.org/10.1056/
scribing patterns of antihypertensive drugs. Clinical Hypertension NEJMoa2006923
22:1–8. https://doi.org/10.1186/s40885-016-0042-0 Martinez-Rojas MA, Vega-Vega O, Bobadilla NA (2020) Is the kidney a
Kai H, Kai M (2020) Interactions of coronaviruses with ACE2, angioten- target of SARS-CoV-2? Am J Physiol Renal Physiol 318:F1454–
sin II, and RAAS inhibitors—lessons from available evidence and F1462. https://doi.org/10.1152/ajprenal.00160.2020
insights into COVID-19. Hypertens Res 43:648–654. https://doi. Miesbach W (2020) Pathological role of angiotensin II in severe COVID-
org/10.1038/s41440-020-0455-8 19. TH Open 4:e138–e144. https://doi.org/10.1055/s-0040-1713678
Kalil GZ, Haynes WG (2012) Sympathetic nervous system in obesity- Moreno-P O, Ramirez JM, Kenneally L, Perdiguero M, Andres M, Navarro
related hypertension: mechanisms and clinical implications. M, Ruiz-Torregrosa P, Boix V, Gil J, Merino E (2020) Hypokalemia
Hypertens Res 35:4–16. https://doi.org/10.1038/hr.2011.173 as a sensitive biomarker of disease severity and the requirement for
Kaseb AO, Mohamed YI, Malek AE, Raad II, Altameemi L, Li D, Kaseb invasive mechanical ventilation requirement in COVID-19 pneumo-
OA, Kaseb SA, Selim A, Ma Q (2021) The impact of angiotensin- nia: a case series of 306 Mediterranean patients. Int J Infect Dis 100:
converting enzyme 2 (ACE2) expression on the incidence and se- 449–454. https://doi.org/10.1016/j.ijid.2020.09.033
verity of COVID-19 infection. Pathogens 10:3. https://doi.org/10. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, Hou C, Wang H, Liu J,
3390/pathogens10030379 Yang D, Xu Y, Cao Z, Gao Z (2020) Role of angiotensin-converting
Kawabe Y, Mori J, Morimoto H, Yamaguchi M, Miyagaki S, Ota T, enzyme 2 (ACE2) in COVID-19. Crit Care 24:422–432. https://doi.
Tsuma Y, Fukuhara S, Nakajima H, Oudit GY, Hosoi H (2019) org/10.1186/s13054-020-03120-0
ACE2 exerts anti-obesity effect via stimulating brown adipose tissue Noreng S, Bharadwaj A, Posert R, Yoshioka C, Baconguis I (2018)
and induction of browning in white adipose tissue. Am J Phys Structure of the human epithelial sodium channel by cryo-electron
Endocrinol Metab 317:e1140–e1149. https://doi.org/10.1152/ microscopy. Elife 7:e39340. https://doi.org/10.7554/eLife.39340.
ajpendo.00311.2019 001
Klemens CA, Edinger RS, Kightlinger L, Li X, Butterworth MB (2017) Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM,
Ankyrin G expression regulates apical delivery of the epithelial so- Butany J (2009) SARS-coronavirus modulation of myocardial
dium channel (ENaC). J BiolChem 292(1):375–385. https://doi.org/ ACE2 expression and inflammation in patients with SARS. Eur J
10.1074/jbc.M116.753616 Clin Investig 39:618–625. https://doi.org/10.1111/j.1365-2362.
Kleyman TR, Cragoe EJ Jr (1988) The mechanism of action of amiloride. 2009.02153.x
Semin Nephrol 8(3):242–248 Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli
Kuba K, Imai Y, Nakanishi TO, Penninger JM (2010) Trilogy of ACE2: a N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY (2016)
peptidase in the renin-angiotensin system, a SARS receptor, and a ACE2 deficiency worsens epicardial adipose tissue inflammation
partner for amino acid transporters. Pharmacol Ther 128:119–128. and cardiac dysfunction in response to diet-induced obesity.
https://doi.org/10.1016/j.pharmthera.2010.06.003 Diabetes 65(1):85–95. https://doi.org/10.2337/db15-0399
Kurihara T, Ozawa Y, Ishida S, Okano H, Tsubota K (2012) Renin- Patel S, Rauf A, Khan H, Abu-Izneid T (2017) Renin-angiotensin-
angiotensin system hyperactivation can induce inflammation and aldosterone (RAAS): the ubiquitous system for homeostasis and
Environ Sci Pollut Res (2022) 29:62235–62247 62247

pathologies. Biomed Pharmacother 94:317–325. https://doi.org/10. Undurraga EA, Chowell G, Mizumoto K (2021) COVID-19 case fatality
1016/j.biopha.2017.07.091 risk by age and gender in a high testing setting in Latin America:
Peminda KC, Gardner MJ, Sowers JR (2017) The renin angiotensin al- Chile March–August 2020. Infect Dis Poverty 10:1–11. https://doi.
dosterone system in obesity and hypertension: roles in the org/10.1186/s40249-020-00785-1
cardiorenal metabolic syndrome. Med Clin N Am 101:129–137. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA,
https://doi.org/10.1016/j.mcna.2016.08.009 Solomon SD (2020) Renin-angiotensin-aldosterone system inhibi-
Poulsen SB, Fenton RA (2019) K+ and the renin-angiotensin–aldoste- tors in patients with Covid-19. N Engl J Med 382:1653–1659.
rone system: new insights into their role in blood pressure control https://doi.org/10.1056/NEJMsr2005760
and hypertension treatment. J Physiol 597:4451–4464. https://doi. Vandenbeuch A, Kinnamon SC (2020) Is the amiloride-sensitive Na+
org/10.1113/JP276844 channel in taste cells really ENaC? Chem Senses 45:233–234.
Reaux A, Fournie-Zaluski MC, Llorens-Cortes C (2001) Angiotensin III: https://doi.org/10.1093/chemse/bjaa011
a central regulator of vasopressin release and blood pressure. Trends Villard O, Morquin D, Molinari N, Raingeard I, Nagot N, Cristol JP, Jung
Endocrinol Metab 12(4):157–162. https://doi.org/10.1016/S1043- B, Roubille C, Foulongne V, Fesler P, Lamure S, Taourel P, Konate
2760(01)00381-2 A, Maria ATJ, Makinson A, Bertchansky I, Larcher R, Klouche K,
Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, Boas WWV, Santos Moing VL et al (2020) The plasmatic aldosterone and C-reactive
RAS, Silva ACS (2008) The renin–angiotensin system and diabetes: protein levels, and the severity of Covid-19: the Dyhor-19 study. J
an update. Vasc Health Risk Manag 4(4):787–803 Clin Med 9:1–12. https://doi.org/10.3390/jcm9072315
Richards J, Greenlee MM, Jeffers LA, Cheng KY, Guo L, Eaton DC, Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V,
Gumz ML (2012) Inhibition of αENaC expression and ENaC activ- Rüger H, Göschke R, Stutz S, Fuhrer W, Schilling W, Rigollier P,
ity following blockade of the circadian clock-regulatory kinases Yamaguchi Y, Cumin F, Baum HP, Schnell CR, Herold P, Mah R,
CK1δ/ε. Am J Physiol Renal Physiol 303:F918–F927. https://doi. Bedigian MP (2003) Structure-based design of aliskiren, a novel
org/10.1152/ajprenal.00678.2011 orally effective renin inhibitor. Biochem Biophys Res Commun
Savoia A, Arrabito E, Parente R, Nicoletti C, Madaro L, Battistoni A, 308:698–705. https://doi.org/10.1016/s0006-291x(03)01451-7
Filippini A, Steckelings UM, Touyz RM, Volpe M (2020) Mas
Woolf SH, Chapman DA, Sabo RT, Zimmerman EB (2021) Excess
receptor activation contributes to the improvement of nitric oxide
deaths from covid-19 and other causes in the US, March 1 2020 to
bioavailability and vascular remodeling during chronic AT1R (an-
January 2 2021. JAMA 325:1786–1789. https://doi.org/10.1001/
giotensin type-1 receptor) blockade in experimental. Hypertension
jama.2021.5199
76:1753–1761. https://doi.org/10.1161/hypertensionaha.120.15527
Schütten MTJ, Houben AJHM, de Leeuw PW, Stehouwer CDA (2017) Xie C, Li Q, Li L, Peng X, Ling Z, Xiao B, Feng J, Chen Z, Chang D, Xie
The link between adipose tissue renin-angiotensin-aldosterone sys- L, Dela Cruz CS, Sharma L (2021) Association of early inflamma-
tem signaling and obesity-associated hypertension. Physiology 32: tion with age and asymptomatic disease in COVID-19. J Inflamm
197–209. https://doi.org/10.1152/physiol.00037.2016 Res 14:1207–1216. https://doi.org/10.2147/jir.S304190
Soler MJ, Wysocki J, Batlle D (2013) ACE2 alterations in kidney disease. Yan W, Spruce L, Rosenblatt MM, Kleyman TR, Rubenstein RC (2007)
Nephrol Dial Transplant 28:2687–2697. https://doi.org/10.1093/ Intracellular trafficking of a polymorphism in the COOH terminus
ndt/gft320 of the α-subunit of the human epithelial sodium channel is modu-
Strawn WB, Ferrario CM, Tallant EA (1999) Angiotensin-(1-7) reduces lated by casein kinase 1. Am J Physiol Renal Physiol 293(3):F868–
smooth muscle growth after vascular injury. Hypertension 33:207– F876. https://doi.org/10.1152/ajprenal.00194.2007
211. https://doi.org/10.1161/01.hyp.33.1.207 Yang J, Ma Z, Lei Y (2021) A meta-analysis of the association between
Sumners C, de Kloet AD, Krause EG, Unger T, Steckelings UM (2015) obesity and COVID-19. Epidemiol Infect 149:E11. https://doi.org/
Angiotensin type 2 receptors: blood pressure regulation and end- 10.1017/S0950268820003027
organ damage. Curr Opin Pharmacol 21:115–121. https://doi.org/ Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D (2006)
10.1016/j.coph.2015.01.004 Glomerular localization and expression of angiotensin-converting
Tikellis C, Thomas MC (2012)Angiotensin-converting enzyme 2 (ACE2) enzyme 2 and angiotensin-converting enzyme: implications for al-
Is a key modulator of the renin angiotensin system in health and buminuria in diabetes. J Am Soc Nephrol 17:3067–3075. https://doi.
disease. Int J Pept 2012:1–8. https://doi.org/10.1155/2012/256294 org/10.1681/ASN.2006050423
Tillett RL, Sevinsky JR, Hartley PD, Kerwin H, Crawford N, Gorzalski Yehualashet AS, Belachew TF (2020) ACEIs and ARBs and their corre-
A, Laverdure C, Verma SC, Rossetto CC, Jackson D, Farrell MJ, lation with COVID-19: a review. Infect Drug Resist 13:3217–3224.
Hooser SV, Pandori M (2020) Genomic evidence for reinfection https://doi.org/10.2147/idr.s264882
with SARS-CoV-2: a case study. Lancet Infect Dis 21:52–58. Zhang J, Wang M, Ding W, Wan J (2020) The interaction of RAAS
https://doi.org/10.1016/S1473-3099(20)30764-7 inhibitors with COVID-19: current progress, perspective and future.
Timmermans PB, Duncia JV, Carini DJ, Chiu AT, Wong PC, Wexler Life Sci 257:118142. https://doi.org/10.1016/j.lfs.2020.118142
RR, Smith RD (1995) Discovery of losartan, the first angiotensin II Zhang X, Lewis AM, Moley JR, Brestoff JR (2021) A systematic review
receptor antagonist. J Hum Hypertens 5:S3–S18 and meta-analysis of obesity and COVID-19 outcomes. Sci Rep 11:
Toma I, Kang JJ, Sipos A, Vargas S, Bansal E, Hanner F, Meer E, Peti- 7193. https://doi.org/10.1038/s41598-021-86694-1
Peterdi J (2008) Succinate receptor GPR91 provides a direct link
between high glucose levels and renin release in murine and rabbit
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
kidney. Clinical Investigation 118:2526–2534. https://doi.org/10.
tional claims in published maps and institutional affiliations.
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