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Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183]
www.ijrpp.com
~ 179~
ISSN Print: 2278 – 2648 IJRPP |Vol.3 | Issue 3 | July-Sep-2014
ISSN Online: 2278-2656 Journal Home page: www.ijrpp.com
Research article Open Access
Effects of Vitamin D on Blood Pressure: Vitamin D act as Anti
Hypertensive agent
*Ali Raza Memon1,
Keenjhar Rani2
, Hina Riaz2
, Nasreen Qazi3
, Saira Baloch4
1
Department of Biochemistry, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro,
Sindh, Pakistan
2
Department of Physiology, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro,
Sindh, Pakistan.
3
Department of Pharmacology, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro,
Sindh, Pakistan.
4
Medical Research Centre, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro, Sindh,
Pakistan.
.* Corresponding author: Ali Raza Memon,,
E-mail id: ali.bio.lumhs@gmail.com
ABSTRACT
Aim
The purpose of this study to rule out the role of vitamin D in hypertensive patients.
Methodology
Total 100 hypertensive patients were selected with same age and same disease criteria, they were divided in to two
groups; group A & B, 50 patients in each group. Group A patients were given antihypertensive drugs and group B
patients were given antihypertensive drugs along with vitamin D orally in tablet form.
Results
Blood pressure readings were recorded on 1st
day of visit then after 15 days & on 45 days interval of therapy. It was
observed that there was significantly decline (p< 0.05) in B.P in those patients who were given antihypertensive
drugs along with regularly vitamin D therapy.
Conclusion
From this study we concluded that vitamin D not only the vitamin or hormone but also act like antihypertensive
agent.
Keywords: Hypertension, Vitamin D, Blood Pressure
International Journal of Research in
Pharmacology & Pharmacotherapeutics
Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183]
www.ijrpp.com
~ 180~
INTRODUCTION
Hypertension is counted as the major cause and most
important factor in the development of cardiovascular
diseases worldwide. (1)
The National Health Survey of Pakistan estimated
that hypertension affects 18% of adults and 33% of
adults above 45 years old. In another report, it was
shown that 18% of people in Pakistan suffer from
hypertension with every third person over the age of
40 becoming increasingly vulnerable to a wide range
of diseases. It was also mentioned that only 50% of
the people with hypertension were diagnosed and that
only half of those diagnosed were ever treated. Thus,
only 12.5% of hypertension cases were adequately
controlled. (2)
Vitamin D is named a »vitamin« like vitamin A or C
because of its exogenous source, but without a doubt
it is hormone. Vitamin D is a secosteroid that is made
in the skin byte action of sunlight, or much less
frequently, ingested through diet. During ultraviolet
B radiation, 7- dehydrocholesterol (provitamin D) is
converted to previtamin D, which is converted into
vitamin D. Vitamin D is very rarely found in food. It
can be found in fish like salmonor in fish oils. In
some countries foods like milk or bread products are
fortified with vitamin D, but it is not an important
source of vitamin D. In the liver vitamin D is
converted by the enzyme cytochrome 450 into
calcidol.
This conversion is under low metabolic control.
Calcidolis biologically inert but it is used to
determine vitamin D status because it has a long half-
life, is easily measured, and there is good correlation
between the level of calcidoland some diseases.
There are many reasons for vitamin D deficiency or
insufficiency: skin pigmentation, aging, obesity, lack
of sun exposure, chronic disease, particularly chronic
kidney disease, latitude of residence etc. (2, 3, 4).
In the kidney, calcidol is metabolized by the
enzyme1a-hydroxylase (CYP27B1) to calcitriol, an
active metabolite of vitamin D. The production of
calcitriol is very tightly controlled by calcium and
phosphorus levels, by parathyroid hormone and
fibroblast growth factor 23.Another enzyme in the
kidney, 24-hydroxylase (CYP24), catabolizes
calcidol and calcitriol into biologically inactive
calcitroic acid (2, 3).Calcitriol acts by activating the
vitamin D receptor (VDR), which binds together with
transcription factor RXR in specific regions of DNA
(VDREs, vitamin D response elements) (5). Vitamin
D receptors are widely distributed. In addition to
tissue and organs involved in mineral and bone
metabolism, VDRs are found in vascular smooth
muscle, endothelium, the heart, brain, skin, pancreas,
macrophages etc. Moreover, some cells like
macrophages or vascular cells express 1a-
hydroxylase,i.e. the possibility of converting calcidol
into calcitriol. This extra renal calcitriol is not tightly
controlled and the calcitriol produced in these cells
have local, autocrine or paracrine effect. The
distribution of VDRs and the local production of
calcitriol demonstrate that vitamin D is a pluripotent
hormone involved not only in calcium homeostasis
and bone metabolism. Today, there is much data that
vitamin D deficiency or insufficiency can cause bone
disease, malignancies, metabolic and immunological
diseases, and cardiovascular disease and hypertension
(2, 3, and 4)
Biological links between vitamin D and blood
pressure
The renin-angiotensin-aldosterone system (RAAS) is
a main regulator of blood pressure and plays a critical
role in the regulation of volume and electrolyte
homeostasis. Increased activation of RAAS is
associated with hypertension. It is well known that
renin is produced injuxtaglomerular cells of the
kidney and that it stimulates angiotensin II and
aldosterone production. Their increased production
elevates blood pressure by vasoconstriction and water
retention. Secondary hyperparathyroidism,
commonly seen in vitamin D deficiency, could be the
reason for hypertension. The mechanism is not
completely clear, but it is a well-known association
that high PTH levels affect vascular smooth muscle
cells and increase vascular stiffness and promotes
atherosclerosis. This is very often seen in patients
with chronic kidney disease. (6)
MATERIAL & METHODS
The present study was conducted at the medical OPD
& Medical Research Centre Liaquat University of
Medical & health Sciences Jamshoro Sindh Pakistan.
Total 100 diagnosed hypertensive patients were
Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183]
www.ijrpp.com
~ 181~
selected. All patients with age range from 40 to 50
years of age having hypertension from at least last
two years. They were divided into two groups; group
A & group B, 50 patients in each group. We give beta
blockers or calcium channel blockers as
antihypertensive in group A patients according to
their need and suitable criteria. The same
antihypertensive drugs were given to group B
patients with same dose along with vitamin D orally
in tablet form for 45 days. Vitamin D level was
measured by ELISA technique. For statistical
analysis SPSS version 16 was used.
RESULTS
At the time of first visit the mean systolic B.P of
group A was 155mmHg and of Group B was 150
mmHg and diastolic B.P was 110 mmHg of group A
while 115 mmHg of group B. After 15 days mean
B.P group A, after taking antihypertensive drugs like
Calcium channel blockers and beta blockers the it
was 135/ 100 mmHg , and after 45 days trial it was
130/90 mmHg. On the other hand after 15 days of
antihypertensive therapy along with taken vitamin D
orally in tablet form the mean B.P was 130/100
mmHg and after 45 days therapy it was 120/75
mmHg.
Above results show that there was significantly
decline (p < 0.05) in systolic as well as diastolic B.P
in those patient who taken antihypertensive drugs
along with vitamin D therapy.
Table No: 01 shows the Mean B.P levels in both
groups at the time of 1st
visit, after 15 and 45 days of
therapy along with their significance.
Graph No: 01 shows the mean systolic B.P in both
groups at the time of all three consecutive visits and
graph B represents the mean diastolic B.P in both
groups.
Graphically it shows that vitamin D has effects on
both systolic as well diastolic but diastolic B.P
affected more than systolic with vitamin D therapy.
TABLE NO: 01
GROUP Mean B.P (mmHg)
at the 1St
Visit
Mean B.P (mmHg) after
15 days of therapy
Mean B.P(mmHg) after
45 days of therapy
A (n=50)
Patients only taking anti
hypertensive drugs
155/ 110 135/100 130/90
B (n=50)
Patients taking antihypertensive
along with vitamin D
150/115 130/100 120/75 *
(* = P value < 0.05)
Graph A: Systolic B.P. of patients of both groups on their three different recordings.
0
20
40
60
80
100
120
140
160
180
1st 2nd 3rd
A
B
Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183]
www.ijrpp.com
~ 182~
Graph B. Diastolic B.P. of patients of both groups on their three different recodings.
DISCUSSION
Vitamin D has important role to maintain blood
pressure especially arterial pressure. Most of
population of Pakistan suffering from deficient
values of vitamin D or near to normal but not the
normal values due to different hereditary and
environmental factors. Experimental evidence shows
that calcitriol inhibits renin synthesis in the kidney. In
a very good study Li et al. demonstrated that vitamin
D, i.e. calcitriol, is a potent inhibitor of renin
synthesis (7). They showed that renin expression and
plasma angiotensin II production is increased in VDR
receptor-null mice, leading to hypertension, cardiac
hypertrophy and increased water intake. In wild mice,
i.e. Mice with intact VDR receptors, the inhibition of
calcitriol synthesis also led to increase in renin
expression, whereas calcitriol injection led to renin
suppression. Kong et al. have demonstrated that this
action of calcitriol on juxtaglomerular cells, i.e.
inhibition of renin expression, is independent of
calcium and PTH (8). Moreover, Zhou et al. in a few
experimental studies have demonstrated that defect in
the 1a-hydroxylase gene, i.e. local production of
calcitriol in some cells led to hypertension, left
ventricular hypertrophy and systolic dysfunction (9).
Tomaschitz A et al. evaluated the concentration of
plasma renin, angiotensin 2 and calcidol and
calcitriol in a large cohort of patients (LURIC study)
(10). In 3,296 subjects a steady increase of plasma
renin concentration across a declining concentration
of calcidol or calcitriol was observed. They
concluded that in humans a lower level of calcidol or
calcitriol is related to the up regulation of RAAS.
Obviously, there are enough results showing negative
relationship between calcidol or calcitriol levels and
RAAS activity. There are also auto mechanisms
involved in the relationship between blood pressure
and vitamin D. the present study also show the
positive effects of vitamin D therapy along with
antihypertensive drugs. These results strongly
support that vitamin D act also as antihypertensive
drug.
REFERENCES
[1] Kannel WB. Blood pressure as a cardiovascular risk factor. J Am Med Assoc.1996;275(20):1571–1576.
[2] FahadSaleem, Azmi Ahmad Hassali, and AsrulAkmalShafie.Hypertension in Pakistan: time to take some
serious action Br J Gen Practiccejun:2010, 60 (575), pp: 449 -450.
[3] Zhang R, Naughton DP. “Vitamin D in health and disease:current perspectives. Nutrition J, 2010; 9: pp:
65–78.
0
20
40
60
80
100
120
140
1st 2nd 3rd
A
B
Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183]
www.ijrpp.com
~ 183~
[4] HolichM F, Chen T C. Vitamin D deficiency: a worldwideproblem with health consequences. Am J
ClinNutr, 2008. 87 (suppl):pp: 1080–1086.
[5] WU-Wongj R. VitaminDreceptor: a highly versatile nuclearreceptor. Kidney2007, 72:pp: 237–239.
[6] Pilz S, Tomaschitz A, Ritz E, Pieber T R. Vitamin D status and arterial hypertension: a systematic review.
Nat Rev Cardiol, 2009. 6: pp: 621–630.
[7] LI C J, Kong J, Wei M, Chen Z-F, Liu Q S, Cao L-P. 1,2-dihydroxyvitamin D3 is a negative endocrine
regulator of therenin-angiotensin system. J ClinInves, 2002, 110:pp:229–238.
[8] Kong J, Qiao G, Zhang Z Z, Liu SQ. Targetedvitamin D receptor expression in juxtaglomerular cells
suppressesrenin expression independent of parathyroid hormone and calcium.Kidney Int2008, 74:pp:1577–
1581.
[9] Zhoucl,Lufx,Cao KJ. Calcium-independent and 1,25(OH) 2D3-dependent regulation of rhe renin-
angiotensin system in1a-hydroxylase knockout mice. Kidney Int2008; 74:pp:170–179.
[10]Tomaschitza, Pilz S, Ritzeet al.Independent associationbetween 1,25-dihydroxyvitamin D, 25-
hydroxyvitamin D andthe renin-angiotensin system The Ludwigshafen risk and cardiovascular(LURIC)
study.ClinChimActa.2010,411:pp:1354–13 60.

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Effects of Vitamin D on Blood Pressure: Vitamin D act as Anti Hypertensive agent

  • 1. Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183] www.ijrpp.com ~ 179~ ISSN Print: 2278 – 2648 IJRPP |Vol.3 | Issue 3 | July-Sep-2014 ISSN Online: 2278-2656 Journal Home page: www.ijrpp.com Research article Open Access Effects of Vitamin D on Blood Pressure: Vitamin D act as Anti Hypertensive agent *Ali Raza Memon1, Keenjhar Rani2 , Hina Riaz2 , Nasreen Qazi3 , Saira Baloch4 1 Department of Biochemistry, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro, Sindh, Pakistan 2 Department of Physiology, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro, Sindh, Pakistan. 3 Department of Pharmacology, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro, Sindh, Pakistan. 4 Medical Research Centre, Liaquat University of Medical & Health Sciences (LUMHS) Jamshoro, Sindh, Pakistan. .* Corresponding author: Ali Raza Memon,, E-mail id: ali.bio.lumhs@gmail.com ABSTRACT Aim The purpose of this study to rule out the role of vitamin D in hypertensive patients. Methodology Total 100 hypertensive patients were selected with same age and same disease criteria, they were divided in to two groups; group A & B, 50 patients in each group. Group A patients were given antihypertensive drugs and group B patients were given antihypertensive drugs along with vitamin D orally in tablet form. Results Blood pressure readings were recorded on 1st day of visit then after 15 days & on 45 days interval of therapy. It was observed that there was significantly decline (p< 0.05) in B.P in those patients who were given antihypertensive drugs along with regularly vitamin D therapy. Conclusion From this study we concluded that vitamin D not only the vitamin or hormone but also act like antihypertensive agent. Keywords: Hypertension, Vitamin D, Blood Pressure International Journal of Research in Pharmacology & Pharmacotherapeutics
  • 2. Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183] www.ijrpp.com ~ 180~ INTRODUCTION Hypertension is counted as the major cause and most important factor in the development of cardiovascular diseases worldwide. (1) The National Health Survey of Pakistan estimated that hypertension affects 18% of adults and 33% of adults above 45 years old. In another report, it was shown that 18% of people in Pakistan suffer from hypertension with every third person over the age of 40 becoming increasingly vulnerable to a wide range of diseases. It was also mentioned that only 50% of the people with hypertension were diagnosed and that only half of those diagnosed were ever treated. Thus, only 12.5% of hypertension cases were adequately controlled. (2) Vitamin D is named a »vitamin« like vitamin A or C because of its exogenous source, but without a doubt it is hormone. Vitamin D is a secosteroid that is made in the skin byte action of sunlight, or much less frequently, ingested through diet. During ultraviolet B radiation, 7- dehydrocholesterol (provitamin D) is converted to previtamin D, which is converted into vitamin D. Vitamin D is very rarely found in food. It can be found in fish like salmonor in fish oils. In some countries foods like milk or bread products are fortified with vitamin D, but it is not an important source of vitamin D. In the liver vitamin D is converted by the enzyme cytochrome 450 into calcidol. This conversion is under low metabolic control. Calcidolis biologically inert but it is used to determine vitamin D status because it has a long half- life, is easily measured, and there is good correlation between the level of calcidoland some diseases. There are many reasons for vitamin D deficiency or insufficiency: skin pigmentation, aging, obesity, lack of sun exposure, chronic disease, particularly chronic kidney disease, latitude of residence etc. (2, 3, 4). In the kidney, calcidol is metabolized by the enzyme1a-hydroxylase (CYP27B1) to calcitriol, an active metabolite of vitamin D. The production of calcitriol is very tightly controlled by calcium and phosphorus levels, by parathyroid hormone and fibroblast growth factor 23.Another enzyme in the kidney, 24-hydroxylase (CYP24), catabolizes calcidol and calcitriol into biologically inactive calcitroic acid (2, 3).Calcitriol acts by activating the vitamin D receptor (VDR), which binds together with transcription factor RXR in specific regions of DNA (VDREs, vitamin D response elements) (5). Vitamin D receptors are widely distributed. In addition to tissue and organs involved in mineral and bone metabolism, VDRs are found in vascular smooth muscle, endothelium, the heart, brain, skin, pancreas, macrophages etc. Moreover, some cells like macrophages or vascular cells express 1a- hydroxylase,i.e. the possibility of converting calcidol into calcitriol. This extra renal calcitriol is not tightly controlled and the calcitriol produced in these cells have local, autocrine or paracrine effect. The distribution of VDRs and the local production of calcitriol demonstrate that vitamin D is a pluripotent hormone involved not only in calcium homeostasis and bone metabolism. Today, there is much data that vitamin D deficiency or insufficiency can cause bone disease, malignancies, metabolic and immunological diseases, and cardiovascular disease and hypertension (2, 3, and 4) Biological links between vitamin D and blood pressure The renin-angiotensin-aldosterone system (RAAS) is a main regulator of blood pressure and plays a critical role in the regulation of volume and electrolyte homeostasis. Increased activation of RAAS is associated with hypertension. It is well known that renin is produced injuxtaglomerular cells of the kidney and that it stimulates angiotensin II and aldosterone production. Their increased production elevates blood pressure by vasoconstriction and water retention. Secondary hyperparathyroidism, commonly seen in vitamin D deficiency, could be the reason for hypertension. The mechanism is not completely clear, but it is a well-known association that high PTH levels affect vascular smooth muscle cells and increase vascular stiffness and promotes atherosclerosis. This is very often seen in patients with chronic kidney disease. (6) MATERIAL & METHODS The present study was conducted at the medical OPD & Medical Research Centre Liaquat University of Medical & health Sciences Jamshoro Sindh Pakistan. Total 100 diagnosed hypertensive patients were
  • 3. Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183] www.ijrpp.com ~ 181~ selected. All patients with age range from 40 to 50 years of age having hypertension from at least last two years. They were divided into two groups; group A & group B, 50 patients in each group. We give beta blockers or calcium channel blockers as antihypertensive in group A patients according to their need and suitable criteria. The same antihypertensive drugs were given to group B patients with same dose along with vitamin D orally in tablet form for 45 days. Vitamin D level was measured by ELISA technique. For statistical analysis SPSS version 16 was used. RESULTS At the time of first visit the mean systolic B.P of group A was 155mmHg and of Group B was 150 mmHg and diastolic B.P was 110 mmHg of group A while 115 mmHg of group B. After 15 days mean B.P group A, after taking antihypertensive drugs like Calcium channel blockers and beta blockers the it was 135/ 100 mmHg , and after 45 days trial it was 130/90 mmHg. On the other hand after 15 days of antihypertensive therapy along with taken vitamin D orally in tablet form the mean B.P was 130/100 mmHg and after 45 days therapy it was 120/75 mmHg. Above results show that there was significantly decline (p < 0.05) in systolic as well as diastolic B.P in those patient who taken antihypertensive drugs along with vitamin D therapy. Table No: 01 shows the Mean B.P levels in both groups at the time of 1st visit, after 15 and 45 days of therapy along with their significance. Graph No: 01 shows the mean systolic B.P in both groups at the time of all three consecutive visits and graph B represents the mean diastolic B.P in both groups. Graphically it shows that vitamin D has effects on both systolic as well diastolic but diastolic B.P affected more than systolic with vitamin D therapy. TABLE NO: 01 GROUP Mean B.P (mmHg) at the 1St Visit Mean B.P (mmHg) after 15 days of therapy Mean B.P(mmHg) after 45 days of therapy A (n=50) Patients only taking anti hypertensive drugs 155/ 110 135/100 130/90 B (n=50) Patients taking antihypertensive along with vitamin D 150/115 130/100 120/75 * (* = P value < 0.05) Graph A: Systolic B.P. of patients of both groups on their three different recordings. 0 20 40 60 80 100 120 140 160 180 1st 2nd 3rd A B
  • 4. Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183] www.ijrpp.com ~ 182~ Graph B. Diastolic B.P. of patients of both groups on their three different recodings. DISCUSSION Vitamin D has important role to maintain blood pressure especially arterial pressure. Most of population of Pakistan suffering from deficient values of vitamin D or near to normal but not the normal values due to different hereditary and environmental factors. Experimental evidence shows that calcitriol inhibits renin synthesis in the kidney. In a very good study Li et al. demonstrated that vitamin D, i.e. calcitriol, is a potent inhibitor of renin synthesis (7). They showed that renin expression and plasma angiotensin II production is increased in VDR receptor-null mice, leading to hypertension, cardiac hypertrophy and increased water intake. In wild mice, i.e. Mice with intact VDR receptors, the inhibition of calcitriol synthesis also led to increase in renin expression, whereas calcitriol injection led to renin suppression. Kong et al. have demonstrated that this action of calcitriol on juxtaglomerular cells, i.e. inhibition of renin expression, is independent of calcium and PTH (8). Moreover, Zhou et al. in a few experimental studies have demonstrated that defect in the 1a-hydroxylase gene, i.e. local production of calcitriol in some cells led to hypertension, left ventricular hypertrophy and systolic dysfunction (9). Tomaschitz A et al. evaluated the concentration of plasma renin, angiotensin 2 and calcidol and calcitriol in a large cohort of patients (LURIC study) (10). In 3,296 subjects a steady increase of plasma renin concentration across a declining concentration of calcidol or calcitriol was observed. They concluded that in humans a lower level of calcidol or calcitriol is related to the up regulation of RAAS. Obviously, there are enough results showing negative relationship between calcidol or calcitriol levels and RAAS activity. There are also auto mechanisms involved in the relationship between blood pressure and vitamin D. the present study also show the positive effects of vitamin D therapy along with antihypertensive drugs. These results strongly support that vitamin D act also as antihypertensive drug. REFERENCES [1] Kannel WB. Blood pressure as a cardiovascular risk factor. J Am Med Assoc.1996;275(20):1571–1576. [2] FahadSaleem, Azmi Ahmad Hassali, and AsrulAkmalShafie.Hypertension in Pakistan: time to take some serious action Br J Gen Practiccejun:2010, 60 (575), pp: 449 -450. [3] Zhang R, Naughton DP. “Vitamin D in health and disease:current perspectives. Nutrition J, 2010; 9: pp: 65–78. 0 20 40 60 80 100 120 140 1st 2nd 3rd A B
  • 5. Ali Raza Memon, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [179-183] www.ijrpp.com ~ 183~ [4] HolichM F, Chen T C. Vitamin D deficiency: a worldwideproblem with health consequences. Am J ClinNutr, 2008. 87 (suppl):pp: 1080–1086. [5] WU-Wongj R. VitaminDreceptor: a highly versatile nuclearreceptor. Kidney2007, 72:pp: 237–239. [6] Pilz S, Tomaschitz A, Ritz E, Pieber T R. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol, 2009. 6: pp: 621–630. [7] LI C J, Kong J, Wei M, Chen Z-F, Liu Q S, Cao L-P. 1,2-dihydroxyvitamin D3 is a negative endocrine regulator of therenin-angiotensin system. J ClinInves, 2002, 110:pp:229–238. [8] Kong J, Qiao G, Zhang Z Z, Liu SQ. Targetedvitamin D receptor expression in juxtaglomerular cells suppressesrenin expression independent of parathyroid hormone and calcium.Kidney Int2008, 74:pp:1577– 1581. [9] Zhoucl,Lufx,Cao KJ. Calcium-independent and 1,25(OH) 2D3-dependent regulation of rhe renin- angiotensin system in1a-hydroxylase knockout mice. Kidney Int2008; 74:pp:170–179. [10]Tomaschitza, Pilz S, Ritzeet al.Independent associationbetween 1,25-dihydroxyvitamin D, 25- hydroxyvitamin D andthe renin-angiotensin system The Ludwigshafen risk and cardiovascular(LURIC) study.ClinChimActa.2010,411:pp:1354–13 60.