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Vitamin D and Vitamin D Receptor: New Insights in the Treatment of Hypertension


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Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis. But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflammation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distributed in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin D and VDR in hypertension has received extensive attention. Hypertension is a disease with high incidence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting renin- angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vascular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with increased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly raise BP and promote target organ damage. Due to the high correlation between vitamin D and hypertension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and protecting against the target organ damage.
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Current Protein and Peptide Science, 2019, 20, 984-995
Vitamin D and Vitamin D Receptor: New Insights in the Treatment of
Lin Lin1, Lei Zhang1, Chao Li1, Zhibo Gai1,* and Yunlun Li1,*
1Shandong University of Traditional Chinese Medicine, 250003 Ji-nan, China
Received: September 28, 2 018
Revis ed: April 29 , 2019
Accepted: June 01 , 2019
Abstract: Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis.
But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflam-
mation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distrib-
uted in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin
D and VDR in hypertension has received extensive attention. Hypertension is a disease with high inci-
dence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have
shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting
renin-angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vas-
cular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with in-
creased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly
raise BP and promote target organ damage. Due to the high correlation between vitamin D and hyper-
tension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The
aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and
protecting against the target organ damage.
Keywords: Vitamin D, vitamin D receptor, hypertension, hypertensive organ damage, therapeutic targets, cardiovascular risk.
The classic function of vitamin D is to promote the intes-
tinal absorption of calcium and maintain skeletal health. In
recent decades, we have found vitamin D receptor (VDR)
exists in almost all human cells and modulates about 3 per-
cent of human genes by activating a specific transcription
program [1]. So more and more attention has been paid to
the role of vitamin D in non-skeletal d iseases, including dia-
betes mellitus, autoimmune disease, cancer and cardiovascu-
lar disease (CVD). It has been showed that vitamin D status
is inversely correlated with higher disease frequency and
disease severity [2], as well as vitamin D deficiency is an
independent risk factor of total mortality [3].
Hypertension is a global public health problem, charac-
terized by high morbidity, high mortality and a mass of com-
plications. World Health Organization reported that one in
three adults worldwide has raised blood pressure (BP), which
causes approximately half of all deaths from heart disease
and stroke. The risk factors of hypertension mainly involve
in obesity, mental stress, high salt diet and so on, meanwhile
there is growing evidence that vitamin D deficiency is asso-
ciated with hypertension and the increased risk of CVD. A
prospective analysis showed that people with low vitamin D
*Address correspondence to these authors at the Shandong University of
Traditional Chinese Medicine, 250003, Ji-nan, China;
Tel: +86-0531-68616038; E-mails: (Y.L.); (Z.G.)
concentrations were three times more likely to have hyper-
tension than those with high vitamin D concentrations [4]. In
hypertension patients, low serum vitamin D levels increase
the risk of CVD by 60% [5]. VDR activation regulates the
activity of the renin-angiotensin-aldosterone system
(RAAS), recovers endothelial function, suppresses inflam-
mation and immune system, all crucial mediators of hyper-
tension and target organ damage. Hence, in this review, we
will summarize the mechanisms of the vitamin D and VDR
in regulating BP, and in addition, gather epidemiologic and
clinical evidence to evaluate the protective effect of vitamin
D and VDR on hypertension.
Vitamin D is a group of fat-soluble molecules, and the
most important of which are vitamin D2 (ergocalciferol) and
vitamin D3 (cholecalciferol). A large amount of vitamin D is
converted as vitamin D3 from 7-dehydrocholesterol after
exposure to ultraviolet-B (UVB) in the skin. Furthermore,
just 10-20% of vitamin D comes from the diet as vitamin D2
or vitamin D3 [6]. Foods rich in vitamin D are mainly cod
liver oil, fish, animal liver, eggs and fortified milk. Also,
some fruits and vegetables are rich in vitamin D, such as
cherry, guava, persimmon, strawberry, red pepper, yellow
pepper, the chin flowers and so on. As natural traditional
Chinese medicine, calculus bovis and Yolk are often used to
treat osteoporosis and chondropathy.
1875-5550/19$58.00+.00 © 2019 Bentham Science Publishers
Regulation of Vitamin D and VDR in Hypertension Current Protein and Peptide Science, 2019, Vol. 20, No. 10 985
After vitamin D enters the body, it is hydroxylated in the
liver to 25-hydroxyvitamin D [25(OH)D, calcidiol], which is
the major circulating form of vitamin D and is accepted to
determine the overall vitamin D status [7]. 25(OH)D is con-
verted by 1α-hydroxylase in the kidney to its bioactive form,
1,25-dihydroxyvitamin D [1,25(OH)2D, calcitriol], which
has much stronger specificity with VDR and is responsible
for most of vitamin D metabolic actions [7]. Although only
the renal 1α-hydroxylase has a significantly promoting effect
to circulating 1,25(OH)2D levels, extrarenal 1α-hydroxylase
is also able to convert 25(OH)D to 1,25(OH)2D. Many other
cell types, such as vascular endothelial cells (EC) and vascu-
lar smooth muscle cells (VSMC), can express 1α -
hydroxylase with subsequent conversion of 25(OH)D to the
local production of 1,25(OH)2D [8]. This local production
and breakdown is not subject to the same feedback controls
as renal production [8], but is significant to the non-skeletal
actions of vitamin D (Fig. 1) [9]. The local production is one
of the reasons why the 25(OH)D is more clinically useful for
accessing vitamin D status than 1,25(OH)2D, and the others
include that the half-life of 25(OH)D is much longer(3 weeks
versus 8 hours) and the circulating concentration is 1000×
higher than 1,25(OH)2D [10].
VDR as a nucleophilic protein, is a biomolecule to medi-
ate 1,25(OH)2D biological effect. In addition to the tradi-
tional vitamin D target organs associated with calcium me-
tabolism, such as intestine, kidney, bone and parathyroid
glands, VDR also exists in the hair follicle, adipose tissue,
cancer cells, the blood lymphatic system, urogenital system
and nervous system [11, 12]. Furthermore, VDRs have been
found in all the major cardiovascular cell types including
cardiomyocytes [13-15], arterial wall cells [16, 17], and im-
mune cells [18, 19]. This suggests that vitamin D is also in-
volved in cellular functions unrelated to calcium metabolism.
VDR is divided into two categories: nuclear vitamin D
receptor (nVDR) and membrane vitamin D receptor
(mVDR). The mediation of VDR is mainly performed by
nVDR, but mVDR may be able to bind different ligands [20,
21]. In the absence of ligands, nVDR is used with cosuppres-
sor to bind to the vitamin D response elements (VDREs) of
target DNA and inhibit gene transcription. When circulating
1,25(OH)2D binds to the nVDR specifically in the nucleus,
nVDR then undergo phosphorylation and conformational
change, thus dissociating from cosuppressor. Activated
nVDR heterodimerizes with the retinoic x receptor (RXR)
and then the 1,25(OH)2D-VDR-RXR complex identifies and
binds to VDREs on DNA to regulate the expression of genes
under the function of transcription factors. Therefore, by
controlling the activation of nVDR, vitamin D affects auto-
immunity, tissue inflammation and cellular activity including
cell proliferation, differentiation, apoptosis and angiogenesis
[7, 22]. In addition to generate genomic responses in the tar-
get cells through nVDR, 1,25(OH)2D can interact with th e
mVDR that localized in cav eolae of the plasma membrane to
generate rapid nongenomic responses, which requires only a
few seconds to a few minutes [12, 23]. The rapid nonge-
Fig. (1). The process of vitamin D synthesis and metabolism. 80-90% vitamin D is transformed from 7-dehydrocholesterol in the skin.
Only a small fraction comes from diet, such as fish oil, eggs, fortified milk, etc. And then vitamin D is converted to 25(OH)D and
1,25(OH)2D, which are the major circulating form and bioactive form of vitamin D, respectively. Some extrarenal tissues or cells also ex-
press 1α-hydroxylase and produce local 1,25(OH)2D, which influences the inflammation, some cellular activity and cardiovascular health by
combining with lo cal VDR. While, the circulating 1,25(OH)2D in serum mainly regulates skeletal function.
986 Current Protein and Peptide Science, 2019, Vol. 20, No. 10 Lin et al.
nomic responses involve the rapid intestinal absorption of
Ca2+, secretion of insulin by pancreatic β -cells, opening of
voltage-gated Ca2+ and Cl- channels in osteoblasts, the rapid
migration of EC, stimulates lipogenesis and inhibits lipolysis
3.1. Definition and Risk Factors of Vitamin D Deficiency
It is estimated that about half the world’s total population
have low levels of vitamin D [27]. The vitamin D status is
evaluated by the serum 25(OH)D level because of its higher
stability and concentration than 1,25(OH)2D. The definition
of vitamin D deficiency has been controversial. Most guide-
lines and diagnostic criteria agree that vitamin D deficiency
is defined as serum 25(OH)D level below 20 ng/mL (50
nmol/L), and insufficiency is between 20-30 ng/mL (50-75
nmol/L) [27-30]. The North American Institute of Medicine
defines vitamin D deficiency as serum 25(OH)D level below
12 ng/mL (30 nmol/L) [31]. In the first international confer-
ence on controversies in vitamin D, 25(OH)D concentrations
below 12 ng/mL (30 nmol/L) was considered to increase risk
of rickets and osteomalacia, while 25(OH)D concentrations
between 20-50 ng/mL (50-125 nmol/L) seem to be sufficient
in the general population for skeletal health [32].
The risk factors of vitamin D deficiency involve in in-
adequate exposure to sunlight, season, latitude, time of day,
race, sex, skin pigmentation, sunscreen use, aging, obesity,
and sedentary lifestyle, as well as others. [27, 33] Sunlight is
essential for vitamin D synthesis. The researchers found that
mean 25(OH)D concentration was lower in blood samples
collected in winter/spring than in those collected in sum-
mer/fall [34]. Moreover, compared with other races, black
participants have the lowest vitamin D levels [35]. The rea-
son is that people with black skin absorb more UVB in the
melanin, therefore, require more sun exposure to produce
same amounts of vitamin D. Gender also has an impact on
vitamin D status. Female gender is independently associated
with severe vitamin D deficiency, and hypovitaminosis D is
associated with more aggressive coronary atherosclerosis in
women but not in men [36]. What’s more, it has been shown
that percentage of body fat was closely related to vitamin D
deficiency [37]. A survey showed that 76% of obese children
had insufficient vitamin D [38]. And Blum et al. found that
vitamin D concentration in serum was significantly lower
than in subcutaneous fat tissue [39]. This is because adipose
tissue contains VDR so that vitamin D is stored in adipose
tissue, which leads to the reduced bioavailability [40].
3.2. Cro ss-sectional and Epidemiologic Studies
Vitamin D deficiency is highly prevalent all over the
world, especially in the Middle-East and Asia [41]. Although
people far from the equator are more likely to suffer from
vitamin D deficiency, the prevalence is not low in areas with
low latitudes and abundant sunshine [42, 43]. In a large sim-
ple Middle Eastern study of 60,979 patients from 136 coun-
tries with yearlong sunlight, 82.5% of subjects suffer vitamin
D insufficiency [43]. Serum vitamin D levels vary widely
among ethnic groups. A survey about vitamin D levels in a
multiethnic Asian population showed that the 25(OH)D con-
centration of 76.1% participants is below 30 ng/mL. Com-
pared to Chinese ethnicity, Malay and Indian ethnicities are
closely related to suboptimal 25(OH)D concentration [44].
The proportion of persons with 25(OH)D40 nmol/L is 14-
18% in whole US population, while the ratio is up to 46-60%
in non-Hispanic blacks and reduced to 6-10% in non-
Hispanic whites [45].
Moreover, a large number of studies have shown a link
between vitamin D and hypertension. Anderson et al. found
a high prevalence of vitamin D deficiency in the general
healthcare population and a significant association between
low vitamin D levels and the increased risk of hypertension
[46]. Similar results were found in pregnant women [47]. A
retrospective cross-sectional study of overweight and obese
youth showed 45% subjects were 25(OH)D deficient. What’s
more, lower 25(OH)D levels were associated with the in-
creased systolic BP (SBP) and diastolic BP (DBP) [48].
Vishnu et al. found that SBP decreased by 0.19 mm Hg
among US adults for every 10 nmol/L increase in vitamin D.
The association between the higher vitamin D and lower
SBP differs according to ethnicity and gender. After
race/ethnic and gender stratification, only non-Hispanic
white females and non-Hispanic black females reflect this
association [49]. A Mendelian randomization analysis testi-
fied higher 25(OH)D concentration was correlated with de-
creased BP and reduced odds of hypertension. The results
showed that each 10% increase in genetically instrumented
25(OH)D concentration caused a change of -0.37 mm Hg in
SBP, a change of -0.29 mm Hg in DBP and an 8.1% de-
creased odds of hypertension [50]. A meta-analysis found the
pooled odds ratio of hypertension was 0.73 for the highest
compared with the lowest category of 25(OH)D concentra-
tion [51].
In hypertension patients, vitamin D deficiency is more
common. Zhang et al. showed that in hypertension patients
residing in Xinjiang of China, the mean 25(OH)D concentra-
tion was only 12.3 ng/mL and the prevalence of vitamin D
deficiency (<20 ng/mL) and insufficiency (20-30 ng/mL)
was 87.0% and 10.3%, respectively [52]. Pöss et al. reported
low vitamin D states was associated with a decreased SBP
response in patients with resistant hypertension [53]. In addi-
tion, vitamin D concentration was lower in p atients with
nondipper hypertension than those with dipper hypertension
[54, 55].
3.3. Prospective Studies
Some prospective studies have indicated that lower
25(OH)D levels can independently predict clinically differ-
ence in the odds of subsequently developing hypertension. In
two prospective cohort studies, during 4 years of follow-up,
the risk of incident hypertension in men and women whose
measured plasma 25(OH)D levels below 15ng/mL is 6.13
and 2.67 times, respectively, compared to those with suffi-
cient 25(OH)D [4]. Young women participating in the
Nurses’ Health Study 2 in lowest quartile of plasma
25(OH)D had 1.66 fold increased risk of developing incident
hypertension compared with subjects in the highest quartile
[56]. Among 1,211 male physicians free of hypertension at
baseline, 695 developed hypertension over a mean of 15.2
years follow-up period. Men with lower concentration of
baseline plasma 25(OH)D had a higher risk of developing
hypertension [34].
Regulation of Vitamin D and VDR in Hypertension Current Protein and Peptide Science, 2019, Vol. 20, No. 10 987
4.1. Inhibition Activity of the Renin-angiotensin-
aldosterone System
The RAAS is not only a circulating but a local tissue
hormone system, whose all components have been found in
cardiovascular organs [57, 58]. The main actions of the
RAAS is to regulate the BP and fluid and electrolyte homeo-
stasis [57]. Recently, increasing evidence has manifested that
vitamin D maybe a negative endocrine regulator of the
RASS. Disruption of vitamin D signaling in VDR-/- or
1α(OH)ase-/- [VDR or 1α(OH)ase knockout] mice leads to
hyperreninemia, high BP and cardiac hypertrophy, while
1,25(OH)2D downregulates renin gene expression through a
VDR-dependent, and calcium- and PTH (parathyroid hor-
mone)-independent mechanism, suggesting that vitamin D
has a direct impact on the renin biosynthesis, BP homeosta-
sis and even the regulation of cardiac functions [59-63].
Even in wild-type mice, restraint of 1,25(OH)2D synthesis
also led to an increase in renin gene expression, whereas
1,25(OH)2D injection resulted in renin suppression [59]. Vi-
tamin D affects not only circulating but local tissue RAAS.
Islet RAAS components have a growth trend in VDR-/- mice,
and calcitriol can normalize production of RAAS compo-
nents under high-glucose conditions [64]. Moreover, it has
been confirmed that a number of vitamin D analogs have
ability to inhibit renin expression [65, 66]. As the cyclic
adenosine monophosphate (cAMP)-dependent protein kinase
A signaling pathway is a major regulatory pathway related
with renin production, one of the molecular mechanisms by
which 1,25(OH)2D suppresses renin gene transcription is to
block the activity of the cAMP response element [67].
The relationship between vitamin D and RAAS has also
been studied in clinical trials. Nearly 30 years ago, Burgess
showed an inverse relationship between 1,25(OH)2D and
plasma renin activity (PRA) in high renin essential hyperten-
sion [68]. Over the years, a series of clinical trials have been
carried out, but the results are mixed. A study found that in
the group with vitamin D deficiency, PRA is correlated with
high BP and impaired structural and functional state of myo-
cardium. While, the individuals with optimal level of vitamin
D don’t have these correlation [69]. In essential hypertensive
patients with hypovitaminosis D under constant salt intake
and free from drugs which interfere with RAAS, chronic
VDR stimulation doesn’t decrease BP directly but blunts
systemic RAAS activity, including plasma renin, aldoster-
one, PRA and Ang [70]. In a randomized placebo-
controlled trial, vitamin D supplementation can reduce
plasma aldosterone concentration in patients with arterial
hypertension and 25(OH)D insufficiency, but no effect was
seen for plasma renin concentration or aldosterone to renin
ratio [71]. A positive association between 25(OH)D and the
tissue sensitivity to Ang II in obese hypertensives had been
examined, as tissue sensitivity to Ang II is inversely related
to RAAS activity, suggesting that 25(OH)D deficiency may
enhance tissue RAAS activity in obesity [72]. Though some
studies found that vitamin D had no effect on RAAS activity
[73-75], most of the vivo or vitro experiments have observed
that vitamin D and its analogs suppress the activity of circu-
lating or local RAAS to regulate BP.
4.2. Regulate Function of Endothelium and Vessel Wall
Vascular endothelium is a marker of cardiovascular
health, meanwhile, endothelial dysfunction leads to vaso-
spastic contractions and consequently, elevates BP. In 1990,
it has shown that administration of 1,25(OH)2D will increase
contractile force-generating capacity of resistance arteries by
a direct action on the vascular wall [76]. The direct effect is
the result of VDR being widely distributed in vascular wall
Acute doses of vitamin D to healthy individuals will in-
crease vascular tone and reduce blood flow to tissue during
stressors [77]. A cross-sectional study involved 852 subjects
demonstrated vitamin D and endothelium-independent vaso-
dilation are positively correlated in older women [78]. An-
other found AChmax and percentage change of ACh response
were both lower in the vitamin D deficient group compared
with the nondeficient group, indicating low vitamin D levels
decreased microvascular endothelial-dependent vasodilata-
tion [79]. Furthermore, parental vitamin D deficiency is also
associated with elevated BP levels in th e offspring, which is
caused by lower gene expression in the Panx1 promoter re-
gion and impaired endothelial relaxation in the large vessels
[80]. Vitamin D insufficient was associated with flow-
mediated dilation (FMD) and carotid intima-media thickness
(IMT), which are the indicators of endothelial function and
preclinical atherosclerotic changes in the vascular, respec-
tively [81]. Among individuals in the absence of clinical
disease, serum 25(OH)D is also significantly related to endo-
thelial functions and ventricular and arterial stiffness, re-
flected in the lower reactive hyperemia index [82, 83] and
higher pulse wave velocity with low vitamin D levels [84].
Cholecalciferol therapy to hypertensive or chronic kidney
disease patients with hypovitaminosis D resulted in the in-
creased brachial artery FMD [85], as well as the decreased
endothelial dysfunction biomarkers concentrations [86]. A
recent meta-analysis also found a significant increasement in
FMD following vitamin D supplementation, indicating the
protective effect of vitamin D to endothelial function [87].
A large amount of experiments explained the protective
effect of vitamin D on vascular wall at the cellular and mo-
lecular levels. Vitamin D3 can affect endothelial activation in
the context of cytokine-induced destabilization and inhibit
the destabilizing effects on cell-cell junctions. Importantly,
the barrier-enhancing function of vitamin D3 is not only pre-
sent in its active metabolite- 1,25(OH)2D, but also in the
“inactive” dietary and mono-hydroxylated forms of the vita-
min D as well [88]. Meanwhile, paricalcitol, a VDR activator
(VDRA), restored endothelial integrity, endothelial barrier
function and improved the cell-cell contact by increasing
vascular endothelial-cadherin at intercellular junctions [89].
Once activated by vitamin D, VDR can phosphorylate p38,
AKT and ERK to activate endothelial nitric oxide synthase
(eNOS) [90]. Meanwhile, Andrukhova et al. have proved the
effect of vitamin D as a direct transcriptional regulator of
eNOS [91]. eNOS is the key nitric oxide (NO) synthesizing
enzyme, and the reduced expression of eNOS in VDR mu-
tant mice led to endothelial dysfunction and increased arte-
rial stiffness [91]. Similarly, through creating a model of
endothelial-specific VDR-/- mice, it has showed that vitamin
D and VDR modulated blood vessel relaxation and arterial
988 Current Protein and Peptide Science, 2019, Vol. 20, No. 10 Lin et al.
BP by regulating eNOS expression and phospho-vasodilator-
stimulated phosphoprotein levels [92]. Furthermore, vitamin
D could facilitate angiogenesis in EC by increasing VEGF
expression and pro-matrix metalloproteinases (MMP)-2 ac-
tivity [93]. Wong et al. found that 1,25(OH)2D decreases
endothelium-dependent contractions in the aorta of the spon-
taneously hypertensive rat (SHR) by reducing calcium influx
into the EC and suppressing the production of endothelium-
derived contracting factors [94]. Zoccali et al. found serum
phosphate has a bearing on the beneficial effect of paricalci-
tol on endothelial function, indicating the endothelium pro-
tective effect by VDRA may be potentiated by controlling
phosphate at lower levels [95].
4.3. Reduce Vascular Oxidative Stress and Inflammation
Reactive Oxidative Species (ROS) are important intracel-
lular signals for vascular cells growth. Oxidative stress, a
state of ROS being excessive activated, is associated with
vascular diseases, such as hypertension and atherosclerosis.
Oxidative stress suppresses VDR expression in EC, which
could be prevented by 1,25(OH)2D [96]. In an Ang cellular
model of hypertension, vitamin D improved endothelial
function by increasing bioavailable NO, reversing the imbal-
ance between NO and peroxynitrite (ONOO-) concentrations,
as well as reducing oxidative and nitroxidative stress [97].
Calcitriol can reduce oxidative stress by regulating transcrip-
tion of the radical generating and scavenging enzymes in-
stead of scavenging radical directly. Calcitriol improved the
impaired endothelium-dependent relaxations in renal arteries
by preventing ROS over-production and regulating a series
of oxidative stress-related proteins and superoxide dismu-
tase. The results were substantiated in hypertensive patients,
normotensive patients and SHR whatever in vivo or vitro
[98]. Cholecalciferol effectively decreased liver oxidative
stress index and improved serum total antioxidant capacity,
thus suppressing oxidative stress-mediated vascular compli-
cations [99]. Valcheva et al. have indicated that VDR
knockout in mice increased local production of Ang II in the
vascular wall, which is a mediator of oxidative stress,
prompting premature senescence. Vitamin D prevented
VSMC premature senescence by suppressing the local pro-
duction of Ang II and downstream free radicals [100].
Inflammation plays a negative role in endothelial func-
tion and vascular remodeling of hypertension patients. Pari-
calcitol and calcitriol suppressed the expression of inflamma-
tory markers, involved in IL-6, IL-8 and NF-κB [101, 102].
Calcitriol blunted the advanced glycation end products
(AGEs) -induced elevation of NF-κB-p65 DNA binding ac-
tivity to neutralize the deleterious actions of AGEs on EC
activities [103]. Tumor necrosis factor-α (TNF-α) is a pro-
inflammatory cytokine, promoting endothelial dysfunction
with subsequent arterial stiffness. TNF-α increased tissue
factor (TF) expression and procoagulant activity in VSMC,
which can be blunted by vitamin D to inhibit the inflamma-
tion-induced thrombotic state [104]. Ohsawa et al. also
found that 1,25(OH)2D and its potent analogs have antico-
agulant effects in monocytic cells by downregulating TF
expression, upregulating thrombomodulin (TM) expression
and counteracting the effects of TNF and oxidized low den-
sity lipoprotein (oxLDL) [105]. Atherosclerotic plaque in the
aorta of ApoE-deficient mice can be prevented by paricalci-
tol and enalapril, due to the amelioration of inflammatory
and oxidative aortic injury. What’ more, the therapy that
paricalcitol combin ed with enalapril affords greater protec-
tion against atherosclerosis than either drug alone [106].
4.4. Improve Insulin Sensitivity
Insulin contributes to regulation of vascular function and
vasomotor balance. Insulin resistance, an independent risk
factor for primary hypertension, is a pathophysiological re-
sponse of tissue cells to the decrease of insulin sensitivity
and/or reactivity. Some studies have found that insulin resis-
tance and insulin sensitivity are closely associated with BP
and hypertension [107-109]. According to data, increased
insulin sensitivity by one unit reduced the risk of hyperten-
sion by 10% [107]. The correlation between insulin sensitiv-
ity and vascular dilatory function has also been proven [110].
Furthermore, Daniel et al. found that acute hyperinsulinemia
caused by insulin resistance can significantly blunt or delay
renal sodium excretion in hypertensive patients [111].
Meanwhile, hyperinsulinemia is relevant with arterial stiff-
ness [112]. Insulin resistance destroys glucose and lipid me-
tabolism [113, 114], causes endothelial dysfunction and acti-
vates the RAAS [115], which all lead to atherosclerosis and
ultimately hypertension. The evidences suggest that improv-
ing insulin sensitivity is an important measure to control BP
and improve vascular injury.
Low vitamin D levels is associated with insulin resis-
tance [116]. Vitamin D deficiency contributes to the morbid-
ities of diabetes mellitus and hypertension in obese children
and adolescents [116]. A recently study found that vitamin D
deficiency enhanced postprandial insulin concentrations and
homeostatic model assessment insulin resistance values in
female rats. Moreover, the deficiency of vitamin D reduced
sensitivity of the coronary arterio lar wall to insulin, which is
a common cause of the diminished coronary arteriole relaxa-
tion [117]. Increased scavenger receptor expression is con-
sidered as a connection between diabetes and atherosclerosis.
Through suppression of macrophage endoplasmic reticulum
stress and c-Jun N-terminal kinase activation, 1,25(OH)2D
and VDR decreased the expression of scavenger receptors,
improved insulin signaling and restrained oxLDL and acety-
lated LDL (AcLDL)-derived macrophage cholesterol uptake
to prevent foam-cell formation and atherosclerosis [118].
Severe hypertension always causes damage to blood ves-
sels, heart, kidney, brain and other organs. Vitamin D defi-
ciency may aggravate hypertensive organ damage. Several
studies have found that patients with low vitamin D level
increased risk of CVD and its mortality [119-122]. Vitamin
D has a potential benefit in lowering some of cardiovascular
risk markers including BP, total cholesterol, low density
lipoprotein cholesterol, glycated hemoglobin level and arte-
rial stiffness [123-125]. Compared with standard chow, the
double-transgenic rats (dTGR) received vitamin D-depleted
chow for 3 weeks exerted higher SBP, serum creatinine con-
centrations, atrial natriuretic peptide (ANP), brain natriuretic
peptide (BNP) and increased relative heart weights, reflect-
Regulation of Vitamin D and VDR in Hypertension Current Protein and Peptide Science, 2019, Vol. 20, No. 10 989
ing the injury of heart and kidney [126]. Vitamin D defi-
ciency is associated with increased mean pulmonary artery
pressure, increased pulmonary vascular resistance and de-
creased cardiac output in pulmonary hypertension (PH) pa-
tients. While supplying PH rats with vitamin D improved
survival through suppressing right ventricular hypertrophy
[127]. Vitamin D mediated RAAS inhibition and Klotho
expression to achieve a renal protective effects, referring to
depression of proinflammatory, profibrotic, and increased
antioxidative mediators in the kidney tissue [128]. Moreover,
calcitriol improved kidney fibrosis by attenuating vascular
remodeling and ischemia, which are associated with in-
creased expression of endothelin-1, ETBR and eNOS [129].
Hypertension always damages arteries, causing small ar-
tery spasm and vascular wall remodeling, while lumen steno-
sis in turn promo tes the maintenance and development of
hypertension. Vitamin D deficiency is closely related to vas-
cular lesions. Except for higher BP, Ang II infusion to endo-
thelial VDR deficient mice caused increased vascular fibro-
sis and thickening of the aortic wall, as well as a higher level
of fetal genes expression in left ventricular myocardium and
higher expression of hypertrophic marker genes [92]. On a
high fat diet, compared with vitamin D sufficient mice, vita-
min D deficient mice had 2-8-fold greater atherosclerosis in
the thoracic and abdominal aorta, and 2-fold greater athero-
sclerosis in the aortic arch, which is associated with the acti-
vation of macrophage endoplasmic reticulum stress and the
alteration of macrophage subtype [130]. Vitamin D defi-
ciency promoted inward hypertrophic remodeling through
motivating VSMC proliferation, as well as intensified vessel
tone through the elevated vasoconstrictor prostanoid levels,
indicating vitamin D plays a role in cerebral artery geometry
and function [131]. What’s more, in vitro, VDR was transi-
tory expressed during myeloid angiogenic cell differentia-
tion, and calcitriol enhanced differentiation of myeloid pro-
genitor cells into myeloid angiogenic cells and increased the
angiogenic capacity of myeloid angiogenic cell [132].
6.1. Clinical Trials
Vitamin D deficiency is an independent risk factor for
hypertension. Some clinical trials have confirmed that vita-
min D supplementation is beneficial for patients with hyper-
tension, especially those coupling with vitamin D deficiency.
A study from the United States has demonstrated that 3
months of oral vitamin D3 supplementation significantly re-
duced SBP within unselected blacks. For each 1 ng/mL
greater increase in 25(OH)D level, SBP will reduce 0.2-mm
Hg significantly [133]. Sluyter et al. found that high doses
vitamin D supplementation for 1 year lowered central BP
parameters but did not significantly change brachial BP
among adults with vitamin D deficiency. Nevertheless, this
supplementation had little effect on BP parameters in the
total sample [134].
However, the results were not all good. Some trials found
that vitamin D supplementation had no significant effect on
BP in non-hypertensive people [73, 135]. Some other were
conducted in people with hypertension, but also showed the
similar results [136, 137]. These inconsistent results could be
attributed to suboptimal experimental design, research popu-
Fig. (2). The mechanistic link s between vitamin D and BP. Vitamin D and VDR regulate BP mainly by suppressing vasoconstriction and
promoting vasodilatation. Vitamin D decreases the production of RAAS components and the activity of RAAS. What’s more, vitamin D
improves vascular function directly or indirectly. Vitamin D can increase vascular tone. Furthermore, Vitamin D restrains oxidative stress
and inflammation response thus repairing endothelial dysfunction and retarding atherosclerosis. Insulin resistance reduces arteriole relaxa-
tion, which can be suppressed by vitamin D.
990 Current Protein and Peptide Science, 2019, Vol. 20, No. 10 Lin et al.
lation selection, initial BP status, diversity in vitamin D dos-
age, used form of vitamin D component, treatment cycle,
season, or other facgtors. Future trials need to optimize the
experiment design, prolong follow-up periods and take the
effect of metabolism on the biological effects into account.
Importantly, measurement of potential biological or bio-
chemical indexes of vitamin D should be standardized to
allow pooling of research data [32].
6.2. Hypervitaminosis D and Rational Drug Use
Only a few studies have reported that excess vitamin D
supplementation can also cause high BP. In animal studies,
hypervitaminosis D is often used in conjunction with nico-
tine to create models of vascular calcium overload, which
causes isolated systolic hypertension, arterial stiffness and
kidney failure [138-140]. Mirhosseini et al. found both vita-
min D deficiency and toxicity can increase SBP and arterial
stiffness in rats, indicating the dose-response curve of ad-
verse cardiovascular effect to vitamin D was U-shaped [141].
Cases of vitamin D intoxication in human are on the rise,
largely due to the over-the-counter vitamin D supplement.
Patients who take or inject a large amount of vitamin D for a
long time will have hypercalcemia, hyperphosphatemia, kid-
ney stone or renal failure, extensive vascular calcification,
and what’s more, some patients will suffer from hyperten-
sion [142-144].
For the type of vitamin D supplement, vitamin D3 is
more effective in improving serum 25(OH)D concentration
than vitamin D2 [145]. Compared with vitamin D3,
25(OH)D3 supplementation led to a safer, more immediate
and sustained rise in serum 25(OH)D levels, as well as a 5.7-
mm Hg decrease in SBP [146]. About the optimal dose of
vitamin D for lowering BP, a clinical trial found that 2000
international unit (IU) of vitamin D per day as an add-on to
nifedipine showed significant antihypertensive effect [147].
Another showed that 4000IU/d of cholecalciferol are better
than 2000U/d and 1000IU/d [133]. For all this, due to the
difference of individual's sensitivity to vitamin D, the opti-
mal dose should vary with each individual to achieve optimal
plasma 25(OH)D levels. However, both lower and upper
thresholds of plasma 25(OH)D levels for maintaining normal
BP are not clear at present. This still requires further explora-
Increased evidence suggests that vitamin D levels are
closely linked to BP. Through a series of experiments, we
found that vitamin D and VDR regulate BP in many ways
(Fig. 2). Vitamin D deficiency can increase risk of high BP
and aggravate hypertensive organ damage. According to the
evidence provided in this review, vitamin D was more effec-
tive in lowering BP in patients with hypertension and vita-
min D deficiency than in the general population. But vitamin
D can play a role in the physiological mechanisms associated
with BP and CVD in healthy people, involving the inhibition
of RAAS activation, the repair of endothelial function, and
other functions.
In conclusion, vitamin D and VDR play a certain role in
the treatment of hypertension. Whether vitamin D can be
used as a biomarker or a conventional therapeutic drug of
hypertension remains to be tested experimentally. And the
guidelines for vitamin D supplementation in clinical prac-
tices or in people who are at risk for hypertension also need
to be explored.
Not applicable.
This work received support by National Nature Science
Foundation of China grant No’s. 81473653 and 81774242.
The authors declare no conflict of interest, financial or
Declared none.
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... Smooth muscle cells also possess VDR, which expresses the enzyme 1a-hydroxylase. Vitamin D has an antiproliferative effect on smooth muscle cells by inhibiting the enzyme endothelium-dependent DNA synthase and cell proliferation, then the effect on elastogenesis and immunomodulation [27]. Physiological doses of vitamin D inhibit the release of proinflammatory cytokines, adhesion molecules and the proliferation of smooth muscle cells of the blood vessels, which results in the suppression of calcification of the intima and media of blood vessels [27]. ...
... Vitamin D has an antiproliferative effect on smooth muscle cells by inhibiting the enzyme endothelium-dependent DNA synthase and cell proliferation, then the effect on elastogenesis and immunomodulation [27]. Physiological doses of vitamin D inhibit the release of proinflammatory cytokines, adhesion molecules and the proliferation of smooth muscle cells of the blood vessels, which results in the suppression of calcification of the intima and media of blood vessels [27]. ...
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Cardiovascular diseases rank first on the mortality list globally or 31%. The basic measure of prevention in accordance with the recommendations of the World Health Organization is a change in risk lifestyle in terms of diet, physical activity, tobacco and alcohol consumption. Vitamin D was previously recognized as a regulator of calcium and phosphorus ratio, bone remodeling or the main controller of skeletal pathophysiology. However, vitamin D enjoys great interest in clinical and epidemiological research in terms of its possible impact on reducing the risk of cardiovascular diseases. Among other things, vitamin D deficiency is associated with an increased risk of endothelial dysfunction. Although the deficiency has been identified as a risk marker for cardiovascular diseases, the mechanism of action of vitamin D on the path from endothelial dysfunction to cardiovascular diseases has not been fully revealed. The findings in this segment of activity of vitamin D would be significant in terms of reducing morbidity and mortality from cardiovascular diseases.
... VDR is a novel protein that is able to bind 1,25(OH) 2 D 3 and its analogues at sub-nanomolar concentrations in the human genome (Haussler et al., 1997). VDR is not only located in the skeletal system but also widely distributed in other tissues such as the small intestine (Battistini et al., 2020), kidney (Chokhandre et al., 2015), heart (Lin et al., 2019), lung (Wang and Jiang, 2021), pancreas (Wallbaum et al., 2018), liver (Triantos et al., 2021a), and immune cells (Wang et al., 2012b) as well as other cell types (Wang et al., 2012b). VDR is located in the cytosol of VD-target cells (Udomsinprasert and Jittikoon, 2019; Triantos et al., 2021b). ...
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Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas. The incidence of CP is increasing worldwide but the effective therapies are lacking. Hence, it is necessary to identify economical and effective agents for the treatment of CP patients. Vitamin D (VD) and its analogues have been confirmed as pleiotropic regulators of cell proliferation, apoptosis, differentiation and autophagy. Clinical studies show that VD deficiency is prevalent in CP patients. However, the correlation between VD level and the risk of CP remains controversial. VD and its analogues have been demonstrated to inhibit pancreatic fibrosis by suppressing the activation of pancreatic stellate cells and the production of extracellular matrix. Limited clinical trials have shown that the supplement of VD can improve VD deficiency in patients with CP, suggesting a potential therapeutic value of VD in CP. However, the mechanisms by which VD and its analogues inhibit pancreatic fibrosis have not been fully elucidated. We are reviewing the current literature concerning the risk factors for developing CP, prevalence of VD deficiency in CP, mechanisms of VD action in PSC-mediated fibrogenesis during the development of CP and potential therapeutic applications of VD and its analogues in the treatment of CP.
... However, β-carotene did not show any beneficial effect on metabolic syndrome in high-fat fed rats (Poudyal et al., 2010). Administration of vitamin D (calcitriol) in patients with hypertension and heart failure has been shown to exert beneficial effects by inhibiting the renin-angiotensin system and parathyroid hormone secretion, as well as acting directly on vitamin D receptors present in vascular smooth muscle cells, endothelial cells and cardiomyocytes (Nemerovski et al., 2009;Lin et al., 2019). Meta-analysis of several observational studies has revealed that there occurs an inverse relationship between the elevated levels of 25-hydroxyvitamin D (a precursor of calcitriol) and reduction of risk of cardiovascular disease such as myocardial infarction, heart failure and aortic stenosis (Zittermann and Koerfer, 2008;Grandi et al., 2010). ...
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By virtue of their regulatory role in various metabolic and biosynthetic pathways for energy status and cellular integrity, both hydro-soluble and lipo-soluble vitamins are considered to be involved in maintaining cardiovascular function in health and disease. Deficiency of some vitamins such as vitamin A, B6, folic acid, C, D, and E has been shown to be associated with cardiovascular abnormalities whereas supplementation with these vitamins has been claimed to reduce cardiovascular risk for hypertension, atherosclerosis, myocardial ischemia, arrhythmias, and heart failure. However, the data from several experimental and clinical studies for the pathogenesis of cardiovascular disease due to vitamin deficiency as well as therapy due to different vitamins are conflicting. In this article, we have attempted to review the existing literature on the role of different vitamins in cardiovascular disease with respect to their deficiency and supplementation in addition to examining some issues regarding their involvement in heart disease. Although both epidemiological and observational studies have shown some merit in the use of different antioxidant vitamins for the treatment of cardiovascular disorders, the results are not conclusive. Furthermore, in view of the complexities in the mechanisms of different cardiovascular disorders, no apparent involvement of any particular vitamin was seen in any specific cardiovascular disease. On the other hand, we have reviewed the evidence that deficiency of vitamin B6 promoted KCl-induced Ca2+ entry and reduced ATP-induced Ca2+-entry in cardiomyocytes in addition to decreasing sarcolemmal (SL) ATP binding. The active metabolite of vitamin B6, pyridoxal 5′-phosphate, attenuated arrhythmias due to myocardial infarction (MI) as well as cardiac dysfunction and defects in the sarcoplasmic reticulum (SR) Ca2+-transport in the ischemic-reperfused hearts. These observations indicate that both deficiency of some vitamins as well as pretreatments with different vitamins showing antioxidant activity affect cardiac function, metabolism and cation transport, and support the view that antioxidant vitamins or their metabolites may be involved in the prevention rather than the therapy of cardiovascular disease.
... 8,9 In the cardiovascular system, VDR is found in the myocardium and endothelial cells. 10 In vitro, vitamin D inhibits the proliferation and hypertrophy of cardiomyocytes. 11 ...
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Vitamin D deficiency has long been associated with the incidence of cardiovascular disease. It also thought to play a role in the severity of COVID-19 patients. A serum concentration of 25(OH) D < 50 nmol/L (vitamin D deficiency) is found in patient with severe COVID-19 manifestation requiring intensive care. These patients are thought to stem from an uncontrolled complex immune response. The role of vitamin D in the COVID-19 infection reaction is by supporting antimicrobial peptides response in the respiratory epithelium and reducing inflammatory reactions to SARS-CoV-2 infection. Therefore, it can reduce the severity of COVID-19 infection. Vitamin D has also involved in several cardiovascular diseases that could increase the severity of COVID-19 infection; i.e., hypertension, lipid metabolism, atherosclerosis, and heart failure. Vitamin D affects endothelial cell function, thus regulating vasodilatation of dependent endothelial cells. It can prevent atherosclerosis and vascular calcification, which COVID-19 patients are at an increased risk. It also reduces pro-inflammatory cytokines, which has an anti-remodelling effect to reducing the fatality risk of obesity and heart failure among COVID-19 patients. Understanding the importance of avoiding vitamin D deficiency, the fulfilment of daily intake should be taken into account. The recommended daily dose of vitamin D is 200 IU per day for those aged < 50 years, 400 IU per day for those aged 50-70 years and 600 IU for individuals aged > 70 years. It is estimated that for every 100 IU of vitamin D, the 25(OH)D level increases by 2.5 nmol/L.
... General guidelines defining the nutrient requirements of the mouse are available (see below) [10]. Folic acid (folacin), folate pteroyl-L-glutamic acid, pteroyl-L-glutamate, pteroylmonoglutamic acid Coenyzme in single-carbon group (methyl-, methylene-, formyl group) transfer reactions [71] Vitamin B 12 Cobalamin Coenzyme for the methionine synthase and methylmalonyl-CoA mutase [72] Binding to vitamin D receptor acting as a transcription factor; calcium and phosphate homeostasis; immune system; cell proliferation and differentiation; bone formation; innate and adaptive immunity [75,76] Vitamin E α/β/γ/δ-tocopherols, α/β/γ/δ-tocotrienols Antioxidant and radical scavenger; modulator of gene expression; enzyme activity regulator (e.g., protein kinase C) [77] Vitamin K Phylloquinone (vitamin K1), menaquinones MK-4 through MK-10 (vitamin K2) γ-glutamyl carboxylation; relevant in blood coagulation and bone metabolism; modulator of transcriptional activity; agonist of steroid and xenobiotic nuclear receptor; neural stem cell differentiation modulator [78] Based on the heterogeneous character of the different vitamins, their stability is highly variable. Quantitatively deterioration in content over time of vitamins can be affected by many factors, including temperature, moisture, oxygen, light, pH, oxidizing and reducing agents, catalytic activity of metals, mutual damage by other vitamins, detrimental compounds (e.g., sulphur dioxide), or combination of these factors [79]. ...
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The laboratory mouse is the most common used mammalian research model in biomedical research. Usually these animals are maintained in germ-free, gnotobiotic, or specific-pathogen-free facilities. In these facilities, skilled staff takes care of the animals and scientists usually don’t pay much attention about the formulation and quality of diets the animals receive during normal breeding and keeping. However, mice have specific nutritional requirements that must be met to guarantee their potential to grow, reproduce and to respond to pathogens or diverse environmental stress situations evoked by handling and experimental interventions. Nowadays, mouse diets for research purposes are commercially manufactured in an industrial process, in which the safety of food products is addressed through the analysis and control of all biological and chemical materials used for the different diet formulations. Similar to human food, mouse diets must be prepared under good sanitary conditions and truthfully labeled to provide information of all ingredients. This is mandatory to guarantee reproducibility of animal studies. In this review, we summarize some information on mice research diets and general aspects of mouse nutrition including nutrient requirements of mice, leading manufacturers of diets, origin of nutrient compounds, and processing of feedstuffs for mice including dietary coloring, autoclaving and irradiation. Furthermore, we provide some critical views on the potential pitfalls that might result from faulty comparisons of grain-based diets with purified diets in the research data production resulting from confounding nutritional factors.
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The aim of our study was to identify whether vitamin-D deficiency (VDD) can alter the geometry of the coronary-resistance-artery system. Male Wistar rats were divided into vitamin-D-deficient (VD−, n = 10) and vitamin-D-supplemented (VD+, n = 8) groups. After eight weeks, branches and segments of the left-anterior-descending-coronary-artery (LAD) network were analyzed by a video-microscopy technique. Segments were divided into 50 μm-long cylindrical ring units. VDD did not increase the number of morphological abnormalities. The number of segments did not differ between the groups (VD−: 210 and VD+: 224; pooled data of 8 networks). A larger lumen area of branches was found in VD+ group, while 1–4-order branches were lengthier in the VD− group. VD− rats had less rich coronary-resistance-artery networks in terms of 50 µm-long units. (VD−: 6365 vs. VD+: 6602; pooled data of 8 networks). VD+ animals were richer in the 100–350 µm outer diameter range, and VD− animals were richer in the 400–550 µm-diameter units. In VD− rats, 150–200 and 300 µm units were almost missing at higher flow distances from the orifice. Serum vitamin-D alterations caused by dietary changes can affect the geometry of the coronary-artery network, which may contribute to vitamin-D-dependent changes in cardiovascular mortality.
This chapter is organized into two major sections that address issues about the nutritional aspects of (1) gestation and (2) puerperium, based on the best scientific evidence. The recommended tools and methods for nutritional assessment and weight management followed by nutritional requirements during pregnancy and lactation are presented at each section. Adequacy of gestational weight gain and interventions to reduce postpartum weight retention are opportunely contextualized in the present obesity scenario. Recommendations for common situations in prenatal or postnatal care such as digestive symptoms, nutritional deficiencies, pica, hypertensive disorders of pregnancy, diabetes mellitus, and prescription of nutritional supplements are critically discussed. The main nutritional guidelines for adult and adolescent pregnant or lactating women are summarized for use by health professionals in clinical practice. Current topics emerging in the field of maternal and child nutrition are introduced in this chapter: chrononutrition, vegetarianism, DASH diet, e-Health, and early life programming.
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Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 μg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 μg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone (p < 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats.
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The aims of this study were to evaluate: (1) associations of vitamin D with the presence/severity of Hashimoto’s thyroiditis (HT) and (2) correlations of vitamin D with thyroid-related phenotypes. Total 25(OH)D (vitamin D in the text) was measured from stored serum samples of 461 HT patients and 176 controls from a Croatian Biobank of HT patients (CROHT). (1) Vitamin D levels, and proportions of vitamin D deficiency, were compared between HT cases and controls. HT patients were additionally divided into two groups (MILD and OVERT) to take into account HT severity. (2) Correlations between vitamin D and 10 clinical phenotypes in all HT patients and two subgroups of HT patients were tested using the Spearman correlation test. Our analyses were adjusted for age, gender, BMI, smoking status and seasonality of blood sampling. (1) No significant differences in vitamin D levels, or proportions of vitamin D deficiency, were detected between HT patients of all disease stages and controls. However, a nominally significant difference in vitamin D levels between MILD and OVERT subgroups (OR = 1.038, p = 0.023) was observed. Proportions of individuals with vitamin D deficiency during winter–spring were high: all HT cases (64.69%), MILD (60.64%), OVERT (68.7%), controls (60.79%). (2) A nominally significant negative correlation between vitamin D and TSH in all HT patients (r = −0.113, p = 0.029) and a positive correlation between vitamin D and systolic blood pressure in OVERT HT patients (r = 0.205, p = 0.025) were identified. Our study indicates that there is no association between vitamin D and HT; however, there may be a subtle decrease in vitamin D levels associated with overt hypothyroidism.
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Vitamin D, a crucial hormone in the homeostasis and metabolism of calcium bone, has lately been found to produce effects on other physiological and pathological processes genomically and non-genomically, including the cardiovascular system. While lower baseline vitamin D levels have been correlated with atherogenic blood lipid profiles, 25(OH)D supplementation influences the levels of serum lipids in that it lowers the levels of total cholesterol, triglycerides, and LDL-cholesterol and increases the levels of HDL-cholesterol, all of which are known risk factors for cardiovascular disease. Vitamin D is also involved in the development of atherosclerosis at the site of the blood vessels. Deficiency of this vitamin has been found to increase adhesion molecules or endothelial activation and, at the same time, supplementation is linked to the lowering presence of adhesion surrogates. Vitamin D can also influence the vascular tone by increasing endothelial nitric oxide production, as seen in supplementation studies. Deficiency can lead, at the same time, to oxidative stress and an increase in inflammation as well as the expression of particular immune cells that play a pivotal role in the development of atherosclerosis in the intima of the blood vessels, i.e., monocytes and macrophages. Vitamin D is also involved in atherogenesis through inhibition of vascular smooth muscle cell proliferation. Furthermore, vitamin D deficiency is consistently associated with cardiovascular events, such as myocardial infarction, STEMI, NSTEMI, unstable angina, ischemic stroke, cardiovascular death, and increased mortality after acute stroke. Conversely, vitamin D supplementation does not seem to produce beneficial effects in cohorts with intermediate baseline vitamin D levels.
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The 1st International Conference on Controversies in Vitamin D was held in Pisa, Italy June 14‐16, 2017. The meeting's purpose was to address controversies in vitamin D research, review data available to help resolve them and suggest a research agenda to clarify areas of uncertainty. Serum 25‐hydroxyvitamin D (25 (OH)D) concentration, i.e., the sum of 25 (OH)D3 and 25 (OH)D2, remains the critical measurement for defining vitamin D status. Assay variation for 25 (OH) D has contributed to the current chaos surrounding efforts to define hypovitaminosis D. An essential requirement to develop consensus on vitamin D status is that measurement of 25 (OH) D and, in the future, other potential vitamin D biomarkers, e.g., 1α,25 (OH)2D3, 3‐epi‐25 (OH) D, 24,25 (OH)2D3, vitamin D binding protein (DBP), free/bioavailable 25 (OH) D and parathyroid hormone be standardized/harmonized, to allow pooling of research data. Vitamin D Standardization Program (VDSP) tools are described and recommended for standardizing 25 (OH) D measurement in research. In the future, similar methodology, based on National Institute for Standards and Technology (NIST) Standard Reference Materials, must be developed for other candidate markers of vitamin D status. Failure to standardize/harmonize vitamin D metabolite measurements is destined to promulgate continued chaos. At this time, 25 (OH) D values below 12 ng/mL (30 nmol/L) should be considered to be associated with an increased risk of rickets/osteomalacia while 25 (OH) D concentrations between 20‐50 ng/mL (50‐125 nmol/L) appear to be safe and sufficient in the general population for skeletal health. In an effort to bridge knowledge gaps in defining hypovitaminosis D, an international study on rickets as a multifactorial disease is proposed.
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Caudal-type homeobox protein 2 (CDX-2) is an intestine-specific transcription factor (TF), with a polymorphic binding site (Cdx-2, rs11568820, A/G) in the vitamin D receptor gene (VDR). The molecular mechanism underlying Cdx-2 association with conditions like osteoporosis, which depends on intestinal VDR expression and calcium absorption, is believed to be due to higher affinity of CDX-2 for the ancestral A allele compared to the G allele. However, it is unclear why the polymorphism is associated with diseases like tuberculosis, which is dependent on VDR expression in immune cells that do not express CDX-2. This study aimed to explain Cdx-2 variant association with immune-related conditions. We hypothesised that the effect of Cdx-2 polymorphism on VDR expression in monocytes/macrophages, devoid of the CDX-2 TF, is indirect and dependent on circulating 25(OH)D3 and VDR methylation. Primary monocyte/macrophages from healthy donors (n = 100) were activated though TLR2/1 elicitation. VDR mRNA and 25(OH)D3 were quantified by RT-qPCR and LC-MS/MS, respectively. Genotyping and methylation analysis were done by pyrosequencing. AA vs. AG/GG showed reduced levels of 25(OH)D3 (P < 0.010), higher VDR promoter methylation (P < 0.050) and lower VDR mRNA induction (P < 0.050). Analysis of covariance confirmed that the effect of Cdx-2 variants depends primarily on VDR methylation. Thus, VDR methylation may confound association studies linking VDR polymorphisms to disease.
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Background: Prior studies suggest that vitamin D therapy may decrease cardiovascular disease risk in type 2 diabetes (T2DM) by lowering renin-angiotensin system (RAS) activity. However, randomized human intervention studies to evaluate the effect of vitamin D receptor (VDR) agonists on RAS activity are lacking. Objective: The objective of this article is to investigate the effect of direct VDR activation with calcitriol on circulating RAS activity and vascular hemodynamics in T2DM. Methods: A randomized, double-blinded, and placebo-controlled study wherein 18 participants with well-controlled T2DM without chronic kidney disease (CKD) were administered calcitriol or placebo for three weeks was conducted. Outcome measures included plasma renin activity (PRA), serum and urinary aldosterone, mean arterial pressure (MAP) before and after an infusion of angiotensin II, and renal plasma flow (RPF) via para-aminohippurate clearance. Results: Despite an increase in 1,25(OH)2D with calcitriol administration (45.4 to 61.8 pg/ml, p = 0.03) and no change with placebo, there were no significant differences in PRA, serum or urinary aldosterone, baseline and angiotensin II-stimulated MAP, or basal and angiotensin II-stimulated RPF between interventions. Conclusion: In this randomized and placebo-controlled study in participants with T2DM without CKD, calcitriol therapy to raise 1,25(OH)2D levels, when compared with placebo, did not significantly change circulating RAS activity or vascular hemodynamics.
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Background Clinical studies indicate that vitamin D3 improves circulation and may have beneficial effects in hypertension. This study uses nanomedical systems to investigate the role of 1,25-dihydroxy vitamin D3 in the preservation/restoration of endothelial function in an angiotensin II (Ang II) cellular model of hypertension. Methods 1,25-dihydroxy vitamin D3-stimulated nitric oxide (NO) and peroxynitrite (ONOO⁻) concentrations were measured in situ with nanosensors (200–300 mm diameter with a detection limit of 1 nM) in human umbilical vein endothelial cells of African American (AA) and Caucasian American (CA) donors exposed to Ang II. The balance/imbalance between NO and ONOO⁻ concentrations ([NO]/[ONOO⁻]) was simultaneously monitored and used as an indicator of endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction. Results [NO]/[ONOO⁻] imbalance in Ang II-stimulated dysfunctional endothelium was 0.20±0.16 for CAs and 0.11±0.09 for AAs. Uncoupled eNOS and overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributed to high production of ONOO⁻. Vitamin D3 treatment reversed [NO]/[ONOO⁻] to 3.0±0.1 in CAs and 2.1±0.1 in AAs – exceeding that observed in normal endothelium. Vitamin D3 restored uncoupled eNOS and endothelial function by increasing cytoprotective NO and decreasing the cytotoxic ONOO⁻. The beneficial effect of vitamin D3 is associated with a favorable rate of NO and ONOO⁻ release, restoration of the [NO]/[ONOO⁻] and the overall decrease in the overexpression of eNOS, inducible nitric oxide synthase and NADPH oxidase. This effect of vitamin D3 may prove to be beneficial in the treatment of hypertension and other cardiovascular diseases, including heart failure, myocardial infarction, vasculopathy, stroke and diabetes.
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The hypothesis that vitamin D (25(OH)D) insufficiency plays a role in occurring of various disease has led to a rise in requests of dosages and to an increase of health-care costs. 25(OH)D insufficiency is associated with increased risk of cardiovascular disease and hypertension in many studies. Animal studies demonstrated that 25(OH)D insufficiency activates renin angiotensin system but corresponding humans data are limited. The aim of the study was to document relationship between 25(OH)D, blood pressure, and renin angiotensin system in hypertensive subjects. In all, 248 hypertensive individuals, 46.8 years (±14), were hospitalized for an etiological assessment of hypertension in this cross-sectional study over two calendar years. 25(OH)D, plasma renin activity, and aldosterone were determined in stringent conditions and blood pressure was measure. Statistical analyses were carried out to analyze the association between 25(OH)D, blood pressure, and renin angiotensin system using linear and logistic regressions with adjustments on relevant variables. In all, 80% of the studied population had a 25(OH)D insufficiency. There were no significant association between 25(OH)D and levels of systolic or diastolic blood pressure, plasma renin activity, and aldosterone whatever the statiscal method used after adjustment. 25(OH)D is not associated with blood pressure and renin angiontensin component in hypertensive subjects. These results corroborate the interventional studies which are for a large majority negatives. A new definition of the 25(OH)D insufficiency in general population is necessary.
We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression.
Background: Uraemia induces endothelial cell (EC) injury and impaired repair capacity, for which the underlying mechanism remains unclear. Active vitamin D (VD) may promote endothelial repair, however, the mechanism that mediates the effects of VD in chronic kidney disease are poorly understood. Thus, we investigated uraemia-induced endothelial damage and the protection against such damage by active VD. Methods: We applied electric cell-substrate impedance sensing (ECIS) to study real-time responses of human ECs exposed to pooled uraemic and non-uraemic plasma with or without the addition of active VD. The effects of indoxyl sulphate and p-cresol were tested in non-uraemic plasma. Structural changes for vascular endothelial (VE)-cadherin and F-actin were assessed by immunostaining and quantified. Results: The exposure of ECs to uraemic media significantly decreased endothelial barrier function after 24 h. Cell migration after electrical wounding and recovery of the barrier after thrombin-induced loss of integrity were significantly impaired in uraemic-medium stimulated cells and cells exposed to indoxyl sulphate and p-cresol. This effect on ECIS was dependent on loss of cell-cell interaction. Mechanistically, we found that EC, exposed to uraemic media, displayed disrupted VE-cadherin interactions and F-actin reorganization. VD supplementation rescued both endothelial barrier function and cell-cell interactions in ECs exposed to uraemic media. These events were associated with an increment of VE-cadherin at intercellular junctions. Conclusions: Our data demonstrate a potentially clinically relevant mechanism for uraemia-induced endothelial damage. Furthermore, active VD rescued the uraemic medium-induced loss of cell-cell adhesion, revealing a novel role of active VD in preservation of endothelial integrity during uraemia.
Hyperandrogenic state in females is accompanied with metabolic syndrome, insulin resistance and vascular pathologies. A total of 67%–85% of hyperandrogenic women suffer also from vitamin D deficiency. We aimed to check a potential interplay between hyperandrogenism and vitamin D deficiency in producing insulin resistance and effects on coronary resistance arteries. Adolescent female rats were divided into four groups, 11–12 animals in each. Transdermal testosterone-treated and vehicle-treated animals were kept either on vitamin D-deficient or on vitamin D-supplemented diet for 8 weeks. Plasma sexual steroid, insulin, leptin and vitamin D plasma levels were measured, and oral glucose tolerance test was performed. In coronary arterioles, insulin receptor and vitamin D receptor expressions were tested by immunohistochemistry, and insulin-induced relaxation was measured in vitro on isolated coronary resistance artery segments. Testosterone impaired glucose tolerance, and it diminished insulin relaxation but did not affect the expression of insulin and vitamin D receptors in vascular tissue. Vitamin D deficiency elevated postprandial insulin levels and homeostatic model assessment insulin resistance. It also diminished insulin-induced coronary arteriole relaxation, while it raised the expression of vitamin D and insulin receptors in the endothelial and medial layers. Our conclusion is that both hyperandrogenism and vitamin D deficiency reduce sensitivity of coronary vascular tissue to insulin, but they do it with different mechanisms.
Objective: We hypothesised that vitamin D has a beneficial renal protective effect from diabetic nephropathy (DN). Methods: Four rat groups were included: normal control (control), type 2 diabetes for eight weeks (DM), treated group with angiotensin receptor blocker losartan (DM + L), and vitamin D-treated group started from the onset of diabetes (DM + Vit D). Results: In the both treated groups, we found a significant (p < .05) reduction in the renal pro-inflammatory and profibrotic markers induced by diabetes. Vitamin D caused more reduction in monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGFβ-1), and renin–angiotensin levels that gave better kidney function compared to the DM + L group. Conclusion: Vitamin D may have a valuable role in the renal protective effect from DN, this may occur via expression of its VDR, Klotho and blocking renin–angiotensin activation, so vitamin D should be considered as a target in renal prophylactic measures against DN.