Content uploaded by Parisa Esmaeili
Author content
All content in this area was uploaded by Parisa Esmaeili on Oct 08, 2020
Content may be subject to copyright.
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=iarp20
Archives of Physiology and Biochemistry
The Journal of Metabolic Diseases
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iarp20
The benefits of Vitamin D in the COVID-19
pandemic: biochemical and immunological
mechanisms
Hadis Musavi , Omid Abazari , Zeinab Barartabar , Fatemeh Kalaki-Jouybari ,
Mohsen Hemmati-Dinarvand , Parisa Esmaeili & Soleiman Mahjoub
To cite this article: Hadis Musavi , Omid Abazari , Zeinab Barartabar , Fatemeh Kalaki-Jouybari ,
Mohsen Hemmati-Dinarvand , Parisa Esmaeili & Soleiman Mahjoub (2020): The benefits of Vitamin
D in the COVID-19 pandemic: biochemical and immunological mechanisms, Archives of Physiology
and Biochemistry
To link to this article: https://doi.org/10.1080/13813455.2020.1826530
Published online: 08 Oct 2020.
Submit your article to this journal
View related articles
View Crossmark data
REVIEW
The benefits of Vitamin D in the COVID-19 pandemic: biochemical and
immunological mechanisms
Hadis Musavi
a
, Omid Abazari
b
, Zeinab Barartabar
c
, Fatemeh Kalaki-Jouybari
a
, Mohsen Hemmati-Dinarvand
d
,
Parisa Esmaeili
e
and Soleiman Mahjoub
a,f,g
a
Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran;
b
Department of Clinical
Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;
c
Department of Clinical Biochemistry, School
of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran;
d
Department of Clinical Biochemistry and Laboratory Medicine,
Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran;
e
Department of Immunology and Microbiology, Faculty of Medicine,
Kurdistan University of Medical Sciences, Sanandaj, Iran;
f
Cellular and Molecular Biology Research Center, Health Research Institute, Babol
University of Medical Sciences, Babol, Iran;
g
Department of Pathology, University of Kiel, Kiel, Germany
ABSTRACT
In December 2019, a new infectious complication called CoronaVirus Infectious Disease-19, briefly
COVID-19, caused by SARS-COV-2, is identified in Wuhan, China. It spread all over the world and
became a pandemic. In many individuals who had suffered SARS-COV-2 infection, cytokine storm starts
through cytokine overproduction and leads to Acute Respiratory Syndrome (ARS), organ failure, and
death. According to the obtained evidence, Vitamin D (VitD) enhances the ACE2/Ang(1–7)/MasR path-
way activity, and it also reduces cytokine storms and the ARS risk. Therefore, VitD intake may be bene-
ficial for patients with SARS-COV-2 infection exposed to cytokine storm but do not suffer hypotension.
In the present review, we have explained the effects of VitD on the renin-angiotensin system (RAS)
function and angiotensin-converting enzyme2 (ACE2) expression. Furthermore, we have reviewed the
biochemical and immunological effects of VitD on immune function in the underlying diseases and its
role in the COVID-19 pandemic.
ARTICLE HISTORY
Received 1 July 2020
Revised 4 September 2020
Accepted 15 September 2020
Published online 1 October
2020
KEYWORDS
Vitamin D; ACE2; cytokine
storm; SARS-COV-2
Introduction
A new coronavirus subfamily (SARS-COV-2) was found and
identified in Wuhan, China (Chen et al.2020) in December
2019, provoked a coronavirus-associated pneumonia
(CoronaVirus Infectious Disease-19, briefly COVID-19), and
increased every moment. Today, most laboratories have con-
firmed that COVID-19 cases in the world exceed 31 million
so far (www.WHO.INT, 2020).
In many people with SARS-COV-2 infection, cytokine
storm could be seen as a result of a cytokine overproduction
that leads to ARS, organ failure, and finally, death.
Researchers have focussed on preventing and treating the
disease consistently. Nonetheless, no specific vaccine or anti-
viral drug has been developed for COVID-19 yet. VitD in
modulating the immune response in infectious and auto-
immune diseases is well known. There is a hypothesis that
VitD supplements could be useful for treatment of COVID-19.
In the present review, we tried to clarify the role of VitD in
patients with SARS-COV-2 infection. We explained the effect
of VitD on the RAS function, ACE2 expression, and the bio-
chemical and immunological roles of VitD on
immune function.
VitD, ACE2, and SARS-COV-2
SARS-COV-2 utilises the same SARS-CoV mechanism (through
the ACE2 receptor and the TMPRSS2 protease) to enter host
cells (Hoffmann et al.2020). Recent studies have claimed
that 83% of the cells that express ACE2 are alveolar type II
epithelial cells. These cells act as a repository role for cell
invasion, and ACE2 expression increases SARS-COV-2 prolifer-
ation (Zhang et al.2020b). Also located ACE2 on the intes-
tinal epithelial cells’lumen surface can be a SARS-COV-2
entranceway into the body (Yang et al.2007, Imai et al.
2008, Hashimoto et al.2012, Chai et al.2020, Pan et al.2020,
Young et al.2020). Studies also have claimed that the heart,
liver, bile ducts, and pancreas are affected by high corona-
virus infection due to the increased ACE2 expression (Chai
et al.2020, Huang et al.2020a, Walls et al.2020, Zhang et al.
2020a)(Figure 1).
The ACE/Ang II/AT1R axis and the ACE2/Ang 1–7/MasR
axis are two axes of the RAS maintaining hemostasis in
humans. ACE2 prevents the classic RAS system’s activation
and protects the body against high blood pressure, inflam-
mation, diabetes, cardiovascular disease, and fibrosis (Cheng
et al.2020). Previous studies have suggested that the devel-
opment of SARS-CoV infection disrupts the physiological
CONTACT Soleiman Mahjoub smahjoub20@gmail.com, s.mahjoub@mubabol.ac.ir Head of Health Products and Food Research Center & Head of Clinical
Biochemistry Department, Cellular and Molecular Biology Research Center, Health Research Institute, School of Medicine, Babol University of Medical Sciences,
Ganjafrooz avenue, Babol 4717647745, Iran; Department of Pathology, University of Kiel, Michaelisstrasse 11, Kiel, D-24105, Germany
ß2020 Informa UK Limited, trading as Taylor & Francis Group
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY
https://doi.org/10.1080/13813455.2020.1826530
balance between the ACE/ACE2 and Ang II/Ang-1–7, leading
damage to the lungs. Viral infection of SARS-CoV into the
mice body increases Ang II in lung tissue and causes severe
damage. Investigations have demonstrated that ACE2 and
AT2 receptors protect mice from respiratory problems caused
by the SARS-CoV virus, Whereas ACE, Ang II, and AT1 recep-
tors impair lung function in mouse models (Imai et al.2005,
Kuba et al.2005, Bao et al.2020, Hoffmann et al.2020, Wan
et al.2020, Zhou et al. 2020).
Treatment with various concentrations of VitD represses
the AT1 receptor expression and renin biosynthesis but sig-
nificantly enhances ACE2 expression (Cui et al.2019). On the
other hand, VitD reduces Ang II production (Dong et al.
2012, Freundlich et al.2014, Garc
ıaet al.2014) and prevents
the development of the respiratory disease by increasing the
expression of ACE2 (Li et al.2004, Imai et al.2005,Liet al.
2016). Diversely, animal studies have shown that 1a-hydroxy-
lase deficiency increases RAS activity that is downregulated
with the treatment of VitD (Zhou et al.2008, Shi et al.2017).
In summary, VitD administration strengthens ACE2, Ang 1–7,
and MasR axis expression and, VitD alters the balance among
ACE/Ang II/AT1 and ACE2/Ang 1–7 to the appropriate and
protective side (Jiang et al.2014, Santos et al.2018, Cui et al.
2019, Leffa et al.2019). These effects indicate the decisive
role of VitD in protection against lung infection in COVID-19.
VitD, RAS blockers, and SARS-COV-2
VitD plays a pivotal role in regulating systolic blood pressure,
renal function, and glycemic control in diabetic patients (Li
et al.2004, Andersen et al.2015, Leung 2019).
Hypovitaminosis D is associated with pathophysiology issues
and target organ disorders, including liver, renal, cardiovas-
cular, acute respiratory distress syndrome, and exacerbated
hypertensive and inflammation (Kong and Li 2003,
Hansdottir et al.2008, Andersen et al.2015,Xuet al.2017,
Leung 2019, Liu et al.2019, Parizadeh et al.2019).
Suppressing the RAS activity as an essential pharmacological
tool effectively treats and improves inflammation and meta-
bolic syndrome (Zhang et al.2014,Xuet al.2017, Cui et al.
2019, Leung 2019). Many evidence has verified that there is
a marked correlation among the effect of VitD and RAS activ-
ity; in this way, VitD prevents progressive acute lung injury
via elevating the expression and function of the RAS mem-
bers such as ACE2 mRNA (Xu et al.2017) and a protective
effect in the hypertensive brain. Although evidence between
VitD and RAS association in the brain is limited (Imai et al.
2005, Groves et al.2014, Cui et al.2019), chronic VitD deple-
tion may negatively affect the function of various organs
because VitD regulates hypertension and inflammation by
inhibiting RAS activity and suppressing the renin synthesis
(Dong et al.2012, Gowrisankar and Clark 2016, Cremer et al.
2018, Legarth et al.2018, Santos et al.2018, Cui et al.2019,
Leung 2019). In summary, One of the basic mechanisms in
protecting the kidneys and cardiovascular system by VitD is
inhibition of the RAS. Clinical studies have shown significant
therapeutic results of VitD analogs in renal and cardiovascu-
lar diseases (Li 2012).
New hypotheses have emerged in treating patients with
COVID-19, which has led to various studies and theories
Figure 1. The virus may enter cells by binding to the ACE2 receptor. The appropriate viral performance depends on the receptor expression and its distribution.
The virus can infiltrate the body through the nose and mouth and eventually via the lungs’airways. Alveolar type II (AECII) epithelial cells comprise about 83% of
the cells expressing ACE2. Besides the lungs (Zhang et al.2020b), ACE2 is also available in intestinal epithelial cells through the lumen’s surface, and the gut can
be another route for the virus to enter the body (Pan et al. 2020, Young et al.2020). The entered virus infects providers’ACE2 organs, including the heart, kidneys,
brain, liver, and pancreas (Chai et al.2020, Huang et al.2020a, Walls et al. 2020, Zhang et al.2020a, Wadman et al.2020).
2 H. MUSAVI ET AL.
about inhibiting RAS and angiotensin receptors in these
patients (Wu and Mcgoogan 2020). Patients with diabetes,
hypertension, proteinuria, chronic kidney disease, cerebrovas-
cular disease, and coronary heart abnormalities are usually
treated with RAS blockers, including angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin receptor blockers
(ARBs) (Fang et al.2020). Recent trials have proved that ACE
inhibitors and ARBs alter the expression of ACE2 and its
effect on the heart and kidneys (Ferrario et al.2005, Soler
et al.2009, Wang et al.2016). Studies have verified that
SARS-COV-2 infection downregulates the ACE2 and leads to
increased toxicity of Ang II accumulation resulting in acute
respiratory syndrome and myocarditis (Hanff et al.2020, Sun
et al.2020). In patients with COVID-19, an increase and accu-
mulation of Ang II develop inflammatory cytokines and cause
severe damage. Recent experiments show that ACEI/ARB
remedy reduces inflammatory cytokines and reduces the risk
of pneumonia and heart disease in patients. Therefore, the
ACEI/ARB prescription may be efficacious in COVID-19
patients (Hsu et al.2020).
The relation between ACE2-receptor and SARS-COV-2 is a
sensitive subject, as earlier reports on the disease suggested,
avoidance of ACE/ARB inhibitors leads to potentially cata-
strophic effects on cardiopathic patients (Zheng et al.2020).
However, ARBs amplify ACE2 receptors, which may augment
the virus entrance into cells. Based on initial reports from
China and subsequent evidence that arterial hypertension
may be associated with increased risk of mortality in hospi-
talised COVID-19 infected subjects, hypotheses have been
put forward to suggest a potential adverse effect of ACE-
inhibitors or ARBs (De Simone 2020). However, these agents’
effect on patients with COVID-19 is unknown and requires
further stud (Gurwitz 2020). On the other hand, the
American and European Heart Association have ordered
patients with heart failure, high blood pressure, and ischae-
mic heart disease to continue taking these drugs (Tan and
Aboulhosn 2020). Therefore, it can be stated that VitD can
also be effective as a RAS inhibitor in treating underlying
patients with COVID-19.
Biochemical roles of VitD in the immune system
As the main components of the diet, vitamins have an essen-
tial effect on the innate and acquired immune system.
Among different Vitamins, VitD has potent effects on the
immune system; The active form of VitD is calcitriol
(1,25(OH)
2
VitD3). Calcitriol regulates antimicrobial peptides
productions, including cathelicidin and defensin, that control
the natural intestine microbiota floor and supports intestinal
barriers (Clark and Mach 2016). Immune system cells such as
monocytes, neutrophil, and NK cells produce defensins and
cathelicidins as antimicrobial peptides that protect the
immune system. In this regard, the expression of the anti-
microbial peptide is increased under the influence of VitD
(Wang et al.2004). Furthermore, it protects the respiratory
system against infection. It can also increase proteins’expres-
sion related to intercellular connections such as connexin-43,
tight junctions, and E-cadherin in epithelial barriers,
protecting the lungs against infection (Gombart 2009).
Moreover, VitD improves renal epithelial (Mihajlovic et al.
2017) and cornea epithelial barriers (Yin et al.2011). It has
also been confirmed that receptors of VitD are found on
monocytes, macrophages, and it has also been verified that
calcitriol leads to enhance mobility and phagocytosis in mac-
rophages. Activated macrophages cause monocytes’differen-
tiation into the tissue macrophages via calcitriol synthesis
(Wu et al.2018). Macrophages increase the generation of
TNF cytokine and phagocytosis in the presence of VitD and
call and accumulate immune cells such as neutrophils to
inflammation sites and stimulate them to kill microbes (Abu-
Amer and Bar-Shavit 1994). Furthermore, VitD controls inter-
feron (IFN) generation; it increases the production capacity
of oxidative reactions in macrophages against pathogens.
IFNs are considered as immune mediators between innate
and acquired immune system. IFN-c, the most potent stimu-
lant for the macrophages’activation, subsequently causes
increased cellular immunity, augmented intracellular patho-
gen elimination, superoxide production, and expression of
the inflammatory and anti-inflammatory cytokines genes
(Topilski et al.2004). It also inhibits T cells’proliferation by
suppressing the IL-2 production, and it changes the response
from Th1 to Th2 cells. VitD implants lymphocytes into the
skin and produces chemokines. VitD endeavours in the hom-
ing process and production of dermal chemokines in which
the precursor form of the VitD3 produced by sunlight,
absorbed by the dendritic cells, and transformed into the
active form, 1–25(OH)2 D3 via D3 hydroxylase enzymes in
the kidneys and liver and transferred to secondary organs
and by affecting on T-cells, causes increased expression of
CCR10 chemokine receptors on them (Sigmundsdottir et al.
2007). Another function of VitD is inhibition of the prolifer-
ation, differentiation, and production of antibodies from B
cells; besides, VitD, along with the suppression of develop-
ment and maturation of the dendritic cells, decreases expres-
sion of the molecules such as MHC-II and auxiliary
stimulative molecules, including B7 and CD40 on these cells
and therefore declines cytotoxicity of TCD8 cells (Saeed
et al.2016).
Elsewhere, VitD deficiency activates the RAS pathway
through inducing TGFB-1. Another pathway inhibited by 1,25
(OH2) VitD is the Wnt/beta-catenin signalling, which has also
been reported as involved in pulmonary fibrosis. Besides,
VitD has an explicit action on autoimmune disease; specific-
ally, it can reduce the risk in developing of: diabetes mellitus
type 1, multiple sclerosis, rheumatoid arthritis, systemic lupus
erythematosus, Crohn’s disease, thyroiditis, psoriasis, poly-
myalgia rheumatic, autoimmune gastritis, and systemic scler-
osis through prevention of onset immune (Panfili et al.2020).
In summary, the immunomodulatory influence of VitD is
shown in Table 1.
VitD function in SARS-COV-2 immunopathogenesis
Based on numerous studies, a significant reason for mortal-
ities in the initial stage of SARS-COV-2 infection is acute
respiratory distress syndrome (ARDS). For instance, based on
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY 3
an examination, in patients with COVID-19 disease, around
14% died due to RDS (Huang et al.2020b). The main immu-
nopathological incident in contamination with SARS-CoV-2,
SARS-CoV, and MERS-CoV is ARDS (Xu et al.2020). A high
load of different cytokines is considered as an essential
mechanism for ARDS. In SARS-CoV infection, secretion of
massive levels of cytokines including IFN-a, IFN-c, IL-1b, IL-6,
IL-12, IL-18, IL-33, TNF-a, TGFb, and chemokines such as
CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10 via immune system
cells are leading to high rate mortality. Similarly, the serum
concentrations of IL-6, IFN-a, and CCL5, CXCL8, CXCL-10 in
persons who had acute MERS-CoV infection were higher
than those subjects with the mild-moderate infection (Min
et al.2016, Huang et al.2020b). The high levels of cytokines
lead to the hyper-inflammatory syndrome, which causes
death in the late stage of SARS-CoV-2 infection, which is pre-
cisely similar to what happens in SARS-CoV and MERS-CoV
infection (Xu et al.2020)(Figure 2).
VitD inhibits the proliferation of T-cells and suppresses
activation of Th1 cells in adaptive immunity. VitD causes cell
differentiation into regulatory T cells by reducing inflamma-
tory cytokines such as IL-17 and 21. On the other hand, VitD
increases anti-inflammatory cytokines, such as IL-10, that play
an essential role in the induction of tolerance in antigen-pre-
senting cells such as dendritic cells (Bscheider and Butcher
2016,Wuet al.2018).
VitD reduces pro-inflammatory cytokines and increases
anti-inflammatory cytokines by activating different immune
system cells. Mostly, T-cells differentiate into subsets of
helper cells, which leads to increased production of cytokines
in cellular immune responses. These cells are often TH1 and
TH2 cells. Along with IL-2 and IFN-cproduction, TH1 cells
form immune response against intracellular pathogens. Also,
Th2 cells fight against pathogens and extracellular microor-
ganisms through secreting cytokines such as IL-5, IL-4, IL-10,
and IL-13. In this regard, VitD suppresses Th1 cell differenti-
ation via the suppression of IL-1 and IFN-cgeneration
(Lemire 1995,Wuet al.2018).
VitD might induce body tolerance against the high vol-
ume of cytokines during SARS-COV-2 infection by inhibiting
cell differentiation to TH17, enhances Treg cells production,
and increases anti-inflammatory cytokines like IL-10, and
inhibits inflammatory cytokine production from macrophages
and monocytes (Kang et al.2012). Hence, Vit D has an
important anti-inflammatory function on the immune system
by reducing the production of pro-inflammatory cytokines
and increasing anti-inflammatory cytokines in immune cells.
Role of VitD as therapeutic agent
VitD has been widely studied as a preventative and thera-
peutic agent for acute respiratory infections in adults and
children. Numerous studies have shown the hypothesis of a
positive correlation between VitD deficiency and the risk of
pulmonary pneumonia (Zhou et al.2020). A recent system-
atic review has examined the role of VitD as an adjunct ther-
apy to antibiotics in paediatric pneumonia (Das et al.2018).
Studies have confirmed that VitD supplements, along with
antibiotics in paediatric with pneumonia, notably decrease
hospitalisation duration. However, it has a weak effect on the
recovery of acute diseases and mortality rates. Evidence
demonstrates the association between VitD levels and oxida-
tive stress and immune system disorders. Based on previous
research, supplements of VitD prevent wheezing in neonates
with parents who suffered asthma and allergies during preg-
nancy and reduce the risk of asthma and cough in the third
decades of the life of pregnant mothers who had consumed
VitD supplementation during pregnancy (Litonjua et al.,
2014, Rahsepar et al.2017, Mohammadi et al.2018, Calder
et al.2020, Kanafchian et al.2020, Von Mutius and Martinez
2020). Another study shows that long-term VitD supplements
consumption reduce adipose tissue inflammation by lower-
ing TNF-alpha levels (Zakharova et al.2019).
In contrast, A new study found that high-dose VitD sup-
plements did not reduce upper respiratory tract viral infec-
tions in healthy younger people (Aglipay et al.2017).
Table 1. The effect of VitD on the RAS, immune system, inflammation, and oxidative stress.
EFFECTS OF VitD
VitD on RAS and ACE2 Regulating hypertension and inflammation via inhibiting RAS activity and suppressing the renin synthesis.
Strengthening ACE2, Ang 1-7, and MasR axis expression.
Alternating ACE/AngII/AT1 and ACE2/Ang1-7 balance to appropriate and protective side.
VitD and the immune system Increased autophagy and apoptosis of infected cells
Further expressing the antimicrobial peptide including cathelicidin and defensing.
Enhancing mobility and phagocytosis in macrophages.
Inhibiting the proliferation, differentiation, and production of antibodies from B cells.
Suppressing development and maturation of the dendritic cells, decreasing expression of MHC-II and auxiliary stimulative
molecules including CD80 and CD40, and declining cytotoxicity of TCD8 cells.
#Th 1/Th 17 T and "Th 2,
#IL-8, IFN-c, IL-12, IL-6, TNF-a, IL-17
stimulation of IL-4, IL-5, IL-10 production
Recognition of viral dsRNA by TLR 3
Inhibiting dendritic cell migration
VitD and inflammation Differentiating cells into regulatory T cells via reducing the production of inflammation.
Increasing the production of anti-inflammatory cytokines such as IL-10.
Inhibiting inflammatory cytokine production through macrophages and monocytes.
VitD and oxidative stress Preventing some chronic disorders including diabetes, cardiovascular and chronic kidney disease.
Regulating oxidative stress via elevating several molecules expression involved in the antioxidant defense system such as
superoxide dismutase, glutathione peroxidase, glutathione, and suppresses the NADPH oxidase expression.
4 H. MUSAVI ET AL.
However, the noneffectiveness of VitD in young people may
be due to the lower prevalence of VitD deficiency than the
elderly and the threshold for the effectiveness of VitD in pre-
venting lung infection. It has been shown that the negative
association between VitD levels and respiratory tract infec-
tions depends on the active form of VitD (1,25-OH2-Vit D)
(Pletz et al.2014).
Also, VitD decreases the risk of epidemic and pandemic
viral infections. Many fact-findings have claimed that a
proper concentration of VitD reduces viral infections resem-
bling dengue, hepatitis B and C viruses, herpes virus, HIV,
respiratory syncytial virus infections, and pneumonia.
Reducing VitD levels to less than 20 ng/ml intensifies the risk
of diseases like influenza. Ecological studies also show that
increasing VitD supplements concentrations reduces the risk
of influenza through winter (Gruber-Bzura 2018). clinical
studies have pointed out that taking Vit D supplementation
was associated with reduced hospitalisation in patients (Han
et al.2016).
Up to now, there is no clear evidence that VitD supple-
ments prevent the severity and mortality of COVID-19. A
recent small cohort study showed the combined protective
effects of VitD, magnesium, and vitamin B12 against SARS-
COV-2 infection severity. Another similar study showed that
daily VitD intake (without additional doses) showed protect-
ive effects against acute respiratory tract infections, especially
in people with VitD deficiency (Ali 2020). VitD supplements
also increase the expression of antioxidant-related genes
(glutathione reductase and glutamate-cysteine ligase) (Lei
et al.2017) and are thought to help prevent infection of
SARS-COV-2 (Wimalawansa 2020).
In young adults, when exposed to SARS-CoV-2 infection,
due to sufficient amounts of VitD, intracellular glutathione
levels increase, and overproduction of ROS and NF-jB and
P38 MAP kinase expression is inhibited. In contrast, VitD defi-
ciency in the elderly leads to increased activity of the p38
MAP kinase/STAT and ROS/NF-Kb pathways in immune cells.
Therefore, older people with severe SARS-CoV-2 infection are
more prone to being exposed to pro-inflammatory factors in
the immune system (Meftahi et al.2020).
According to the latest examinations, an increase in VitD
concentration decreases the prevalence, severity, and mortal-
ity rate of influenza, pneumonia, and COVID-19. In a latter
case, increased consumption of VitD supplements is crucial
in preventing diseases’appearance and spread (Gombart
et al.2020).
Figure 2. The binding of SARS-COV-2 to receptors and its entrance into cells depends on a cellular protease; subsequently, the virus involves the angiotensin-con-
vertase enzyme 2 (ACE2) and cellular TMPRSS2 serine protease for protein S priming. After protease action, SARS / ACE2 binding starts; the ACE2 operation is the
primary determinant of SARS-COV-2 transmission (Hoffmann et al. 2020). Macrophages and dendritic cells process viral antigens and deliver them to CD4þand
CD8þT cells. Activation of T cells causes their cytolytic and pre-inflammatory effects on infected tissues (Meftahi et al.2020).
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY 5
With age, serum VitD receptor levels are decreased
(Bischoff-Ferrari et al.2004), which is not irrelevant in COVID-
19 because mortality in COVID-19 disease increases with age
(Covid and Team 2020, Mirijello et al.2020).
In 2020, it was reported that VitD could suppress the
expression of inflammatory cytokines, including IL-1a, IL-1b,
as well as TNF-a. Therefore, VitD deficiency in old ages may
be associated with increased expression of Th1 cytokines. It
was also reported that half of the COVID-19 patients and the
majority of COVID-19-related deaths were observed in popu-
lation with a higher risk for VitD deficiency (Ebadi and
Montano-Loza 2020).
Another study on VitD and CRP levels shows that
decreased VitD levels lead to increased patient deterioration.
Besides, blood CRP levels are significantly associated with
disease deterioration in patients. The CRP index shows
higher inflammatory cytokines in aging accompanied by VitD
deficiency (Daneshkhah et al.2020). VitD is thought to
reduce the severity of SARS-CoV-2-induced disease, especially
in patients with hypovitaminosis D (Panarese and Shahini
2020). In a study, The majority of COVID-19 patients (66.4%)
had VitD insufficiency (25–50 nmol/L); 37.3% were deficient
(<25 nmol/L), and 21.6% had severe deficiency (15 nmol/L).
VitD deficiency was more prevalent among patients requiring
intensive care units admission, and thus VitD deficiency
might be an under-recognized determinant of illness-severity
(Panagiotou et al.2020).
According to the findings, patients who needed intensive
care units were inadequate in VitD despite being young.
However, the role of VitD as a prophylactic or therapeutic
agent in patients with SARS-CoV-2 infection still needs fur-
ther investigation (Silberstein 2020). However, population
heterogeneity and the dose of VitD should be considered in
determining the preventive and therapeutic function of VitD
in SARS-CoV-2 infection (Fabbri et al.2020).
In summary, a diet containing micronutrients is not con-
ventional in many countries, including industrial countries.
Evidence has revealed that using some micronutrients more
than the recommended daily allowance (RDA) can optimise
the immune system’s function and increase infection resist-
ance. Despite controversial data, evidence, in general, reveals
that a diet containing a mixture of multiple supplements can
help optimise the immune system and decrease infection
risk (Gombart et al.2020)(Figure 3).
Conclusions
The SARS-COV-2 virus infiltrates into human cells by binding
to the ACE2 receptor, where it starts to reproduce. Extensive
destruction occurs in damaged tissues, especially in the
organs with high expression of ACE2. Consequently, acute
lung inflammation, mediated by pro-inflammatory macro-
phages and granulocytes, results in severe pneumonia and,
in many cases, mortality in the affected patients.
Additionally, binding to the ACE2 leads to exhaustion of
receptors and then inhibiting the ACE2/Ang (1–7)/Mas recep-
tor pathway, causing the loss of RAS system balance and
ultimately exacerbating acute pneumonia. Currently, animal
studies have verified that RAS inhibitors can alleviate symp-
toms of severe pneumonia and respiratory failure. However,
there is no absolute and effective cure for COVID-19.
In this review, the impacts of VitD on the renin-angioten-
sin system function and ACE2 expression has been discussed.
Moreover, the biochemical and immunological actions of
VitD on the immune system have been concluded during
the SARS-COV-2 infection. Investigations have shown that
treatment with different concentrations of VitD inhibits AT1
receptor expression and renin biosynthesis but significantly
increases the ACE2 expression and enhances the MasR path-
way. Hence, according to available evidence, it can be stated
that, under controlled–hypertension conditions, VitD-medi-
ated inhibition of ACEI and AT1R can be used to improve
SARS-COV-2 pneumonia in patients. Also, inflammatory
response and mortality could be reduced by inhibiting the
massive production of cytokines. Therefore, it can be sug-
gested that VitD supplements could help improve patients
Figure 3. The relationship between VitD, ACE2, and SARS-COV2 (Cui et al.2019, Hanff et al.2020, Gombart et al. 2020).
6 H. MUSAVI ET AL.
with COVID-19, exposed to high volumes of cytokines with-
out hypotension, protecting them against cardiovascular and
pulmonary complications.
Acknowledgements
We thank Dr. Pejman Hakemi for his help in preparing the figures.
Ethical standards statement
The Ethics Committee of Babol University of Medical Sciences approved
this study (IR.MUBABOL.REC.1399.161).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability
The data that support the findings of this study are available on request
from the corresponding author. The data are not publicly available due
to governmental policy and privacy.
ORCID
Soleiman Mahjoub http://orcid.org/0000-0002-9775-804X
References
Abu-Amer, Y., and Bar-Shavit, Z., 1994. Regulation of TNF-alpha release
from bone marrow-derived macrophages by vitamin D. Journal of cel-
lular biochemistry, 55 (4), 435–444.
Aglipay, M., et al., 2017. Effect of high-dose vs standard-dose wintertime
vitamin D supplementation on viral upper respiratory tract infections
in young healthy children. JAMA, 318 (3), 245–254.
Ali, N., 2020. Role of vitamin D in preventing of COVID-19 infection, pro-
gression and severity. Journal of infection and public health,1390, 1–8.
Andersen, L.B., et al., 2015. Vitamin D depletion aggravates hypertension
and target-organ damage. Journal of the American heart association,4
(2), e001417.
Bao, L., et al., 2020. The pathogenicity of SARS-CoV-2 in hACE2 trans-
genic mice. bioRxiv.
Bischoff-Ferrari, H., et al., 2004. Vitamin D receptor expression in human
muscle tissue decreases with age. Journal of bone and mineral
research: the official journal of the American society for bone and min-
eral research, 19 (2), 265–269.
Bscheider, M., and Butcher, E.C., 2016. Vitamin D immunoregulation
through dendritic cells. Immunology, 148 (3), 227–236.
Calder, P.C., et al., 2020. Optimal nutritional status for a well-functioning
immune system is an important factor to protect against viral infec-
tions. Nutrients, 12 (4), 1181.
Chai, X., et al., 2020. Specific ACE2 expression in cholangiocytes may
cause liver damage after 2019-nCoV infection. bioRxiv.
Chen, N., et al., 2020. Epidemiological and clinical characteristics of 99
cases of 2019 novel coronavirus pneumonia in Wuhan, China: a
descriptive study. The lancet, 395 (10223), 507–513.
Cheng, H., Wang, Y., and Wang, G.Q., 2020. Organ-protective effect of
Angiotensin-converting enzyme 2 and its effect on the prognosis of
COVID-19. Journal of medical virology, 92 (7), 726–730.
Clark, A., and Mach, N., 2016. Role of Vitamin D in the hygiene hypoth-
esis: the interplay between vitamin D, vitamin D receptors, gut micro-
biota, and immune response. Frontiers in immunology, 7, 627.
Covid, C., and Team, R., 2020. Severe outcomes among patients with
Coronavirus Disease 2019 (COVID-19)—United States, February
12–March 16, 2020. Morbidity and mortality weekly report, 69,
343–346.
Cremer, A., et al., 2018. Investigating the association of vitamin D with
blood pressure and the renin-angiotensin-aldosterone system in
hypertensive subjects: a cross-sectional prospective study. Journal of
human hypertension, 32 (2), 114–121.
Cui, C., et al., 2019. Vitamin D receptor activation regulates microglia
polarization and oxidative stress in spontaneously hypertensive rats
and angiotensin II-exposed microglial cells: role of renin-angiotensin
system. Redox biology, 26, 101295.
Daneshkhah, A., et al., 2020. The possible role of Vitamin D in suppress-
ing cytokine storm and associated mortality in COVID-19 patients.
MedRxiv.
Das, R.R., Singh, M., and Naik, S.S., 2018. Vitamin D as an adjunct to anti-
biotics for the treatment of acute childhood pneumonia. Cochrane
database of systematic reviews, 7 (7), CD011597.
De Simone, G., 2020. Position statement of the ESC council on hyperten-
sion on ACE-inhibitors and angiotensin receptor blockers. ESC escar-
dio. Available from: https://www.escardio.org/Councils/Council-on-
Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-
hypertension-on-ace-inhibitors-and-ang.
Dong, J., et al., 2012. Calcitriol protects renovascular function in hyper-
tension by down-regulating angiotensin II type 1 receptors and
reducing oxidative stress. European heart journal, 33 (23), 2980–2990.
Ebadi, M., and Montano-Loza, A.J., 2020. Perspective: improving vitamin
D status in the management of COVID-19. European journal of clinical
nutrition, 74 (6), 856–854.
Fabbri, A., Infante, M., and Ricordi, C., 2020. Editorial –Vitamin D status:
a key modulator of innate immunity and natural defense from acute
viral respiratory infections. European review for medical and pharmaco-
logical sciences, 24 (7), 4048–4052.
Fang, L., Karakiulakis, G., and Roth, M., 2020. Are patients with hyperten-
sion and diabetes mellitus at increased risk for COVID-19 infection?
The lancet respiratory medicine, 8 (4), e21.
Ferrario, C.M., et al., 2005. Effect of angiotensin-converting enzyme inhib-
ition and angiotensin II receptor blockers on cardiac angiotensin-con-
verting enzyme 2. Circulation, 111 (20), 2605–2610.
Freundlich, M., et al., 2014. Paricalcitol downregulates myocardial renin-
angiotensin and fibroblast growth factor expression and attenuates
cardiac hypertrophy in uremic rats. American journal of hypertension,
27 (5), 720–726.
Garc
ıa, I.M., et al., 2014. Vitamin D receptor-modulated Hsp70/AT1
expression may protect the kidneys of SHRs at the structural and
functional levels. Cell stress & chaperones, 19 (4), 479–491.
Gombart, A.F., 2009. The vitamin D-antimicrobial peptide pathway and
its role in protection against infection. Future microbiology, 4 (9),
1151–1165.
Gombart, A.F., Pierre, A., and Maggini, S., 2020. A review of micronu-
trients and the immune system-working in harmony to reduce the
risk of infection. Nutrients, 12 (1), 236.
Gowrisankar, Y.V., and Clark, M.A., 2016. Angiotensin II regulation of
angiotensin-converting enzymes in spontaneously hypertensive rat
primary astrocyte cultures. Journal of neurochemistry, 138 (1), 74–85.
Groves, N.J., Mcgrath, J.J., and Burne, T.H., 2014. Vitamin D as a neuroste-
roid affecting the developing and adult brain. Annual review of nutri-
tion, 34, 117–141.
Gruber-Bzura, B.M., 2018. Vitamin D and influenza—prevention or ther-
apy? International journal of molecular sciences, 19, 2419.
Gurwitz, D., 2020. Angiotensin receptor blockers as tentative SARS-CoV-2
therapeutics. Drug development research, 81 (5), 537–540.
Han, J.E., et al., 2016. High dose vitamin D administration in ventilated
intensive care unit patients: a pilot double blind randomized con-
trolled trial. Journal of clinical & translational endocrinology,4,59–65.
Hanff, T.C., et al., 2020. Is there an association between COVID-19 mortal-
ity and the renin-angiotensin system—a call for epidemiologic investi-
gations. Clinical infectious diseases: an official publication of the
infectious diseases society of America, 71 (15), 870–874.
Hansdottir, S., et al., 2008. Respiratory epithelial cells convert inactive
vitamin D to its active form: potential effects on host defense. Journal
of immunology, 181 (10), 7090–7099.
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY 7
Hashimoto, T., et al., 2012. ACE2 links amino acid malnutrition to micro-
bial ecology and intestinal inflammation. Nature, 487 (7408), 477–481.
Hoffmann, M., et al., 2020. The novel coronavirus 2019 (2019-nCoV) uses
the SARS-coronavirus receptor ACE2 and the cellular protease
TMPRSS2 for entry into target cells. BioRxiv.
Hsu, W.-T., et al., 2020. Effect of renin-angiotensin-aldosterone system
inhibitors on short-term mortality after sepsis: a population-based
cohort study. Hypertension, 75 (2), 483–491.
Huang, C., et al., 2020a. Clinical features of patients infected with 2019
novel coronavirus in Wuhan. The lancet, 395 (10223), 497–506.
Huang, C., et al., 2020b. Clinical features of patients infected with 2019
novel coronavirus in Wuhan. Lancet , 395 (10223), 497–506.
Imai, Y., Kuba, K., and Penninger, J.M., 2008. The discovery of angioten-
sin-converting enzyme 2 and its role in acute lung injury in mice.
Experimental physiology, 93 (5), 543–548.
Imai, Y., et al., 2005. Angiotensin-converting enzyme 2 protects from
severe acute lung failure. Nature, 436 (7047), 112–116.
Jiang, P., et al., 2014. Chronic stress causes neuroendocrine-immune dis-
turbances without affecting renal vitamin D metabolism in rats.
Journal of endocrinological investigation, 37 (11), 1109–1116.
Kanafchian, M., et al., 2020. Status of serum copper, magnesium, and
total antioxidant capacity in patients with polycystic ovary syndrome.
Biological trace element research, 193 (1), 111–117.
Kang, S.W., et al., 2012. 1,25-Dihyroxyvitamin D3 promotes FOXP3
expression via binding to vitamin D response elements in its con-
served noncoding sequence region. Journal of immunology, 188 (11),
5276–5282.
Kong, J., and Li, Y.C., 2003. Effect of ANG II type I receptor antagonist
and ACE inhibitor on vitamin D receptor-null mice. American journal
of physiology regulatory, integrative and comparative physiology, 285
(1), R255–R261.
Kuba, K., et al., 2005. A crucial role of angiotensin converting enzyme 2
(ACE2) in SARS coronavirus-induced lung injury. Nature medicine,11
(8), 875–879.
Leffa, D.T., et al., 2019. Systematic review and meta-analysis of the
behavioral effects of methylphenidate in the spontaneously hyperten-
sive rat model of attention-deficit/hyperactivity disorder. Neuroscience
and biobehavioral reviews, 100, 166–179.
Legarth, C., et al., 2018. The impact of vitamin D in the treatment of
essential hypertension. International journal of molecular sciences,19
(2), 455.
Lei, G.-S., et al., 2017. Mechanisms of action of vitamin D as supplemen-
tal therapy for Pneumocystis pneumonia. Antimicrobial agents and
chemotherapy, 61 (10), e01226–17.
Lemire, J.M., 1995. Immunomodulatory actions of 1,25-dihydroxyvitamin
D3. The journal of steroid biochemistry and molecular biology,53(1–6),
599–602.
Leung, P.S., 2019. The modulatory action of Vitamin D on the
Renin–angiotensin system and the determination of hepatic insulin
resistance. Molecules, 24 (13), 2479.
Li, Y., et al., 2016. Angiotensin-converting enzyme 2 prevents lipopoly-
saccharide-induced rat acute lung injury via suppressing the ERK1/2
and NF-jB signaling pathways. Scientific reports, 6, 27911.
Li, Y.C., 2012. Vitamin D: roles in renal and cardiovascular protection.
Current opinion in nephrology and hypertension, 21 (1), 72–79.
Li, Y.C., et al., 2004. Vitamin D: a negative endocrine regulator of the
renin–angiotensin system and blood pressure. The journal of steroid
biochemistry and molecular biology,89–90, 387–392.
Litonjua, A.A., et al., 2014. The Vitamin D Antenatal Asthma Reduction
Trial (VDAART): rationale, design, and methods of a randomized, con-
trolled trial of vitamin D supplementation in pregnancy for the pri-
mary prevention of asthma and allergies in children. Contemporary
clinical trials, 38 (1), 37–50.
Liu, J., et al., 2019. Meta-analysis of vitamin D and lung function in
patients with asthma. Respiratory research, 20 (1), 161.
Meftahi, G.H., et al., 2020. The possible pathophysiology mechanism of
cytokine storm in elderly adults with COVID-19 infection: the contri-
bution of “inflame-aging. Inflammation research: official journal of the
European histamine research society, 69 (9), 825–815.
Mihajlovic, M., et al., 2017. Role of Vitamin D in maintaining renal epithe-
lial barrier function in uremic conditions. International journal of
molecular sciences., 18 (12), 2531.
Min, C.K., et al., 2016. Comparative and kinetic analysis of viral shedding
and immunological responses in MERS patients representing a broad
spectrum of disease severity. Scientific reports, 6, 25359.
Mirijello, A., et al., 2020. The first, holistic immunological model of
COVID-19: implications for prevention, diagnosis, and public health
measures. Pediatric allergy and immunology, 31 (5), 454–470.
Mohammadi, A., et al., 2018. Immunomodulatory effects of Thymol
through modulation of redox status and trace element content in
experimental model of asthma. Biomedicine & pharmacotherapy., 105,
856–861.
Pan, Y., et al., 2020. Viral load of SARS-CoV-2 in clinical samples. The lan-
cet. infectious diseases, 20 (4), 411–412.
Panagiotou, G., et al., 2020. Low serum 25-hydroxyvitamin D (25 [OH] D)
levels in patients hospitalised with COVID-19 are associated with
greater disease severity. Clinical endocrinology, 93, 508–514.
Panarese, A., and Shahini, E., 2020. Letter: Covid-19, and vitamin D.
Alimentary pharmacology & therapeutics, 51 (10), 993–995.
Panfili, F., et al., 2020. Possible role of vitamin D in Covid-19 infection in
pediatric population. Journal of endocrinological investigation, 15, 1–9.
Parizadeh, S.M., et al., 2019. Association of vitamin D status with liver
and kidney disease: a systematic review of clinical trials, and cross-
sectional and cohort studies. International journal for vitamin and
nutrition research, 28, 1–13.
Pletz, M.W., et al., 2014. Vitamin D deficiency in community-acquired
pneumonia: low levels of 1,25(OH)2 D are associated with disease
severity. Respiratory research, 15, 53.
Rahsepar, M., et al., 2017. Evaluation of vitamin D status and its correl-
ation with oxidative stress markers in women with polycystic ovary
syndrome. International journal of reproductive biomedicine, 15 (6),
345–350.
Saeed, F., et al., 2016. Studying the impact of nutritional immunology
underlying the modulation of immune responses by nutritional com-
pounds –a review. Food and agricultural immunology, 27 (2),
205–229.
Santos, RaS., et al., 2018. The ACE2/Angiotensin-(1-7)/MAS axis of the
renin-angiotensin system: focus on angiotensin-(1–7). Physiological
reviews, 98 (1), 505–553.
Shi, Y., et al., 2017. Chronic vitamin D deficiency induces lung fibrosis
through activation of the renin-angiotensin system. Scientific reports,
7 (1), 1–10.
Sigmundsdottir, H., et al., 2007. DCs metabolize sunlight-induced vitamin
D3 to ‘program’T cell attraction to the epidermal chemokine CCL27.
Nature immunology, 8 (3), 285–293.
Silberstein, M., 2020. Vitamin D: a simpler alternative to tocilizumab for
trial in COVID-19? Medical hypotheses, 140, 109767.
Soler, M.J., et al., 2009. Localization of ACE2 in the renal vasculature:
amplification by angiotensin II type 1 receptor blockade using telmi-
sartan. American journal of physiology. renal physiology, 296 (2),
F398–F405.
Sun, M., et al., 2020. [Inhibitors of RAS Might Be a Good Choice for the
Therapy of COVID-19 Pneumonia]. Zhonghua jie he he hu xi za
zhi ¼Zhonghua jiehe he huxi zazhi ¼Chinese journal of tuberculosis
and respiratory diseases, 43 (0), E014–E014.
Tan, W., and Aboulhosn, J., 2020. The cardiovascular burden of corona-
virus disease 2019 (COVID-19) with a focus on congenital heart dis-
ease. International journal of cardiology, 309, 70–77.
Topilski, I., et al., 2004. The anti-inflammatory effects of 1,25-dihydroxyvi-
tamin D3 on Th2 cells in vivo are due in part to the control of integ-
rin-mediated T lymphocyte homing. European journal of immunology,
34 (4), 1068–1076.
Von Mutius, E., and Martinez, F.D., 2020. Vitamin D Supplementation dur-
ing Pregnancy and the Prevention of Childhood Asthma. The New
England journal of medicine, 382 (6), 574–575.
Wadman, M., et al., 2020. A rampage through the body. Science, 368,
356–360.
Walls, A.C., et al., 2020. Structure, function, and antigenicity of the SARS-
CoV-2 spike glycoprotein. Cell, 181 (2), 281–292.e6.
8 H. MUSAVI ET AL.
Wan, Y., et al., 2020. Receptor recognition by the novel coronavirus from
Wuhan: an analysis based on decade-long structural studies of SARS
coronavirus. Journal of virology, 94 (7), e001247.
Wang, T.-T., et al., 2004. Cutting edge: 1,25-dihydroxyvitamin D3 is a dir-
ect inducer of antimicrobial peptide gene expression. Journal of
immunology, 173 (5), 2909–2912.
Wang, X., et al., 2016. The effects of different angiotensin II type 1 recep-
tor blockers on the regulation of the ACE-AngII-AT1 and ACE2-
Ang(1–7)-Mas axes in pressure overload-induced cardiac remodeling
in male mice. Journal of molecular and cellular cardiology, 97,
180–190.
Wimalawansa, S.J., 2020. Global epidemic Of Coronavirus—Covid-19:
what can we do to minimize risks. European journal of biomedical,7,
432–438.
Wu, D., et al., 2018. Nutritional modulation of immune function: analysis
of evidence, mechanisms, and clinical relevance. Frontiers in immun-
ology, 9, 3160.
Wu, Z., and Mcgoogan, J.M., 2020. Characteristics of and important les-
sons from the coronavirus disease 2019 (COVID-19) outbreak in
China: summary of a report of 72 314 cases from the Chinese Center
for Disease Control and Prevention. JAMA, 323 (13), 1239.
Www.Who.Int. 2020. Infection prevention and control during health care
when COVID-19 is suspected: interim guidance. Available from: http://
www.Who.Int.
Xu, J., et al., 2017. Vitamin D alleviates lipopolysaccharide-induced acute
lung injury via regulation of the renin-angiotensin system. Molecular
medicine reports, 16 (5), 7432–7438.
Xu, Z., et al., 2020. Pathological findings of COVID-19 associated with
acute respiratory distress syndrome. The lancet respiratory medicine,8
(4), 420–422.
Yang, X.-H., et al., 2007. Mice transgenic for human angiotensin-convert-
ing enzyme 2 provide a model for SARS coronavirus infection.
Comparative medicine, 57, 450–459.
Yin, Z., et al., 2011. Vitamin D enhances corneal epithelial barrier func-
tion. Investigative ophthalmology & visual science, 52 (10), 7359–7364.
Young, B.E., et al., 2020. Epidemiologic features and clinical course of
patients infected with SARS-CoV-2 in Singapore. JAMA, 323 (15), 1488.
Zakharova, I., et al., 2019. Vitamin D insufficiency in overweight and
obese children and adolescents. Frontiers in endocrinology, 10, 103
Zhang, C., Shi, L., and Wang, F.-S., 2020a. Liver injury in COVID-19: man-
agement and challenges. The lancet gastroenterology & hepatology,5
(5), 428–430.
Zhang, H., et al., 2020b. Angiotensin-converting enzyme 2 (ACE2) as a
SARS-CoV-2 receptor: molecular mechanisms and potential thera-
peutic target. Intensive care medicine, 46 (4), 586–585.
Zhang, Z., et al., 2014. ACE2/Ang-(1-7) signaling and vascular remodeling.
Science China life sciences, 57 (8), 802–808.
Zheng, Y.-Y., et al., 2020. COVID-19 and the cardiovascular system.
Nature reviews cardiology, 17 (5), 259–260.
Zhou, C., et al., 2008. Calcium-independent and 1,25(OH)2D3-dependent
regulation of the renin-angiotensin system in 1alpha-hydroxylase
knockout mice. Kidney international, 74 (2), 170–179.
Zhou, P., et al., 2020. Discovery of a novel coronavirus associated with
the recent pneumonia outbreak in humans and its potential bat ori-
gin. BioRxiv.
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY 9
