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3 Vitamin D and the Endothelium in General Population and Experimental Studies

3 Vitamin D and the Endothelium in General Population and Experimental Studies

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346



M. Apetrii and A. Covic



Table 20.1 CKD-associated conditions that trigger endothelial dysfunction (ED) and vitamin D

beneficial effects upon the endothelium

Conditions associated with ED in

CKD

Increased RAAS activity and

hypertension

Angiotensin II

Aldosterone

Diabetes

Dyslipidaemia

Inflammation

Secondary hyperparathyroidism

Klotho- FGF23 axis

Uremic toxins

ADMA

p-cresylsulphate

Adipocytokines

Leptin

Resistin

Visfatin



Vitamin D actions upon endothelial functions

1. Improves/recovers eNOS activity

2. Mitigates AGE-induced downregulation of eNOS

3. Antioxidative:

Downregulates NADPH oxydase

Upregulates SOD-1/2

4. Anti-inflamamtory: downregulates vascular

expression of IL-6 and NF-kB

5. Inhibits endothelial cell apoptosis and promotes

survival

6. Promotes endothelial cell migration and proliferation

7. Angiogenesis through the induction of VEGF



ED endothelial dysfunction, CKD chronic kidney disease, RAAS renin angiotensin aldosterone

system, FGF23 fibroblast growth factor 23, ADMA asymmetric dimethylarginine, eNOS endothelial nitric oxide synthase, AGE advanced glycation end-products, NADPH nicotinamide adenine

dinucleotide phosphate oxidase, SOD superoxide dismutase, IL-6 interleukin-6, NF-kB nuclear

factor-kappa B, VEGF vascular endothelium growth factor



collagen and decreased elastin fibers in the ascending aorta [13]. Vitamin D also has

antioxidant effects on the endothelium: in human endothelial cells, reduction of cell

viability and reactive oxygen species (ROS) production due to oxidative stress is

prevented by pretreatment of endothelial cells with 1,25(OH)2D3 [14]. Vitamin D

increases expression of the antioxidant enzyme CuZn superoxide dismutase in

endothelial cells also [16]. The prevention of cell death is mediated by vitamin D

through reduction of apoptotic proteins and promotion of autophagy, resulting in

cell “recycling” [14].

In general population, data from a case-control study performed by Tarcin et al.

[17], pointed out that vitamin D-deficient (below 25 nmol/l) subjects had a significantly lower flow mediated dilatation (FMD) as a marker of impaired endothelial

function compared to the vitamin D-sufficient control group (mean level of 25(OH)D

= 75 nmol/l). Also, FMD significantly increased after vitamin D supplementation in

the vitamin D deficiency group [17, 18]. Vitamin D deficit also contributes to the

development of arterial stiffness: suboptimal serum 25(OH)D levels are independently associated with measures of endothelial function (increased carotid-femoral

pulse wave velocity (PWV) and augmentation index obtained through applanation

tonometry) in asymptomatic subjects, both with and without traditional CV risk

factors. ED induced by vitamin D deficiency is also mediated by vascular inflammation:



20 Vitamin D and Endothelial Function in Chronic Kidney Disease



347



vitamin D levels are inversely correlated with proinflammatory cytokine interleukin-6

(IL-6) expression in endothelial cells and vitamin D deficiency subjects have increased

expression of the proinflammatory NFkB transcription factor [18].

However, contrary to expectations, vitamin D supplementation in deficient

patients with coronary artery disease failed to show any improvement in endothelial

function. It seems that in high-risk patients that are already on medication that targets potential triggers of endothelial dysfunction (angiotensin converting enzyme,

angiotensin receptor blockers, statins), vitamin D correction/supplementation does

not bring any incremental benefit [19, 20].

Other negative effects associated with vitamin D excess include hyperphosphataemia, hypercalcaemia, medial calcification, arterial stiffness and left ventricular

hypertrophy. High levels of vitamin D increases matrix metallo-proteinase-2 expression, which degrades the extracellular matrix, opening the way for endothelial cell

migration [21]. Angiogenesis is also promoted by vitamin D through induction of

VEGF expression in endothelial cells [16].



20.4



Vitamin D and the Endothelium in CKD



Impaired endothelium function is seen across the whole span of CKD, from predialysis patients to ESRD patients on dialysis to renal transplant recipients [22].

Endothelial cell dysfunction is a well-known culprit of cardiovascular morbidity

and it develops in CKD with remarkable frequency. In fact, CV risk rises with the

decline in the eGFR and the key mediator of this inverse relationship seems to be

represented by ED [3]. Altered endothelial function was initially described in endstage renal disease (ESRD) patients on dialysis. Subsequently, studies have shown

that ED is actually present from the early stages of CKD. However, assessing endothelial function is challenging in renal patients since two of the main conditions that

cause renal impairment – hypertension and diabetes – are also associated with

ED. Therefore, it is difficult to establish whether abnormal endothelial function in

CKD is due to renal impairment or it is predominantly a reflection of pre-existing

vascular disease aggravated by CKD [3, 23].

In CKD patients, endothelial function is altered through various mechanisms

(Table 20.1); Traditional risk factors for cardiovascular disease like hypertension or

diabetes are joined by nontraditional risk factors, such as asymmetric dimethylarginine (ADMA), advanced glycation end-products (AGEs), pro-oxidants, all accumulating in CKD, to induce ED via eNOS uncoupling, which results not only in the

down-regulation of NO production, but also generates oxygen free radicals [12].

Mineral bone disorders may play an important role in endothelial function, since

correction of vitamin D, phosphate and FGF23 after renal transplantation correlates

with improved endothelium-dependent vasodilatation [24]. Cross-sectional studies

correlated serum 25(OH)D, 1,25(OH)2D levels with endothelium-dependent

vasodilation in patients with stage 3–4 CKD and in patients with end-stage kidney

disease on dialysis, suggesting that vitamin D may have an active effect on the

vascular system [25].



348



M. Apetrii and A. Covic



The effect of vitamin D analogues on the improvement of endothelial function is

mediated by the recovery of NO activity [26]. In a CKD-like environment in vitro,

calcitriol directly normalizes eNOS activity and also decreases the number of receptors for AGEs on the endothelial cell. Lack of coupling of AGE to their receptors

blunts AGE-mediated down-regulation of eNOS [27]. Also, calcitriol reverses the

function of endothelial cells exposed to a CKD-like environment: calcitriol downregulates the expression of IL-6 and the activity of NFkB, thus having vascular antiinflammatory properties [27]. These in vitro results are further confirmed by animal

models of CKD studies (sub-total nephrectomized rats) with impaired ED defined as

impaired endothelium-dependent vasorelaxation response to acethylcholine [23, 26].

The uremic environment modifies the vascular expression of a wide-range of

genes that regulate oxidative stress, hormone and immune functions, inflammation

and lipid and glucose metabolism (genes that encode apolipoprotein A-IV, fatty acid

binding protein-2, hydroxysteroid dehydrogenase, heat shock protein 1b, etc.)

finally leading to ED. VDR activators ameliorate endothelial functions also by

reversing these changes at the vascular level [23].

In non-dialysis patients, endothelial function deteriorates with eGFR decrease

[22, 28]. However, there are differences regarding the extent of ED between different CKD stages: ESRD patients have the worse endothelial function assessed by

brachial artery FMD compared to pre-dialysis or kidney transplantation patients. At

the same time, it seems that after renal transplantation, endothelial function is

reversed to the pre-dialysis grade of impairment, as FMD does not differ significantly between pre-dialysis CKD and post-transplantation CKD. This is probably

due to remnant kidney function impairment, preceding CV damage and immunosuppression undesirable secondary effects [28].

In observational studies, vitamin D is a significant positive independent predictor

of endothelial function (FMD) in non-diabetic non-dialysis CKD patients as well in

ESRD patients [28–30]. The lowest FMD is seen in vitamin D deficient patients

compared to vitamin D insufficient and vitamin D sufficient patients [31].

Furthermore, vitamin D deficiency is independently associated with markers of

endothelial activation such as vascular cell adhesion molecule-1 (VCAM-1) and

E-selectin in non-dialysis patients [28].

These results coming from cross-sectional studies were further confirmed by

clinical trials. Thus, in non-diabetic CKD patients stage 3–4 with vitamin D deficiency, 6 months supplementation with ergocalciferol significantly improved

endothelium-dependent microcirculatory function assessed at the forearm level,

proving the causal relationship between vitamin D deficiency and ED [32]. Moreover,

ergocalciferol supplementation of CKD patients reduces oxidative stress and tissue

AGE formation, the latter being predictors of CVD in CKD [32]. Also, cholecalciferol administration to non-diabetic, non-dialysis, vitamin D deficient CKD patients

significantly improves FMD and decreases markers of endothelial activation including inter-cellular adhesion molecule-1 (ICAM-1), VCAM-1 and E-selectin [33].

Paricalcitol administration (2 μg/day for 12 weeks) in patients with CKD stages 3–4

resulted in a significant change in FMD compared to the placebo group [34].

However, reported results regarding the endothelial benefits of vitamin D or vitamin

D analogues administration differ between trials. This may be due to differences in



349



20 Vitamin D and Endothelial Function in Chronic Kidney Disease



time of exposure, as paricalcitol administration for only 1 month does not have any

effect over endothelial function, irrespective of dosage (1 μg/day or 2 μg/day) [35].

Also, endothelial function in patients with diabetes mellitus type 2 and CKD did not

improve after paricalcitol administration (1 μg/day for 3 months). This may be due

to low dosage or it can be explained by the confounding effects of medication that

targets endothelial function (anti-hypertensive or anti-diabetic medication) [36].



20.5



Vitamin D and CKD-Associated Conditions That

Predispose to Endothelial Dysfunction



Vitamin D deficiency also predisposes to a wide range of conditions that cause ED

in CKD, thus having indirect effects upon the endothelium (Fig. 20.1).

EDCF

Ca influx in EC



NF-kB



Vitamin D deficiency



AGE activity

on EC



RANTES

Renin gene expression

AT1R



PTH

Dyslipidaemia

HDL-C



Leukocyte

recruitment



RAS



IL-6



LDL-C/HDL-C



klotho



TACE

activation

Ag-II action on EC



FGF-23

TNF-a



ROS



eNOS

eNOS

uncoupling

EC

proliferation



COX-derived

contracting

factors



Impaired

endotheliumdependent

vasodilation



Endothelial dysfunction



Fig. 20.1 Various pathological conditions that link vitamin D deficiency and endothelial dysfunction

in chronic kidney disease. Abbreviations: Ag-II angiotensin II, AGE advanced glycation end products,

AT1R Angiotensin II type 1 receptor, Ca calcium, COX cyclooxygenase, EC endothelial cells, EDCF

endothelial-dependent contracting factors, eNOS endothelial nitric oxide synthase, FGF-23 fibroblast

growth factor 23, HDL-C High density lipoprotein cholesterol, IL-6 interleukin-6, LDL-C low-density

lipoprotein cholesterol, NF-kB nuclear factor k-B, PTH parathormone, RANTES regulated on activation, normal T cell expressed and secreted chemokine, RAAS renin-angiotensin system, ROS reactive

oxygen species, TACE tumor necrosis factor-α converting enzyme, TNF-α tumor necrosis factor



350



20.5.1



M. Apetrii and A. Covic



Diabetes



In type 2 diabetes, low circulating vitamin D levels favor poor glycemic control, and

the reduction of immature endothelial progenitor cells that are involved in endothelial repair and angiogenesis, thus promoting endothelial function impairment [37].

Vitamin D protects against the negative effects of AGE on eNOS activity [38] and

also has antiatherogenic effects by inhibiting foam cell formation [39]. Despite this,

randomized controlled trials (RCT) of diabetic patients with suboptimal serum vitamin D levels (<30 ng/ml) did not show any significant changes induced by vitamin

D repletion regarding circulating endothelial progenitor cells, FMD or blood pressure. However, FMD was significantly ameliorated by vitamin D repletion in a posthoc analysis of diabetic patients that specifically had baseline endothelial dysfunction

[40]. Clinical studies assessed only the circulating 25(OH)D form, while the active

intracellular form is represented by 1,25(OH)2D3. Therefore, vitamin D activation

by 1α-hydroxylase may alter the relationship between 25(OH)D and markers of

arterial function [41]. As mentioned before, it is also possible that in diabetic

patients that are on vasoactive medication, vitamin D supplementation may not further induce any significant change.



20.5.2



Hypertension



One of the main mechanisms that is excessively activated in both hypertension and

CKD having deleterious effects on vasculature is the RAAS [42]. Vitamin D regulates vascular tone through both genomic and non-genomic mechanisms [42, 43].

Through genomic mechanisms, calcitriol negatively regulates renin gene transcription: VDR-bound calcitriol inhibits the interaction between cyclic adenosine monophosphate (cAMP) response element binding and cAMP response element in the

renin gene promoter, thus inhibiting the transcription of renin gene [44]. Further on,

calcitriol down-regulates angiotensin II receptor 1 (AT1R) expression in renal arteries, thus blunting the deleterious effects induced by angiotensin II binding to its

receptor: in both renal and systemic arteries, vitamin D is responsible for a reduction in angiotensin II-induced ROS excessive generation [43]. ROS promote endothelium dysfunction and finally hypertension: [1] ROS alter eNOS activity, being

responsible for eNOS uncoupling and thus for impaired NO-dependent endothelial

function, ROS promote the expression of cyclooxygenases-derived contracting factors in the endothelium [3, 45, 46]. Also by genomic regulation, calcitriol downregulates the expression of oxidative-stress associated enzyme, NADPH oxidase in

renal arteries. The vascular anti-oxidative action of calcitriol also comprises upregulation of SOD-1 and SOD-2 enzymes in renal arteries. The effects of calcitriol

on NADPH oxidase and SOD expression may partially be mediated by the downregulation of AT1R, as AT1R activation is responsible for ROS production. Thus, by

regulating RAAS and ROS production, vitamin D protects both kidney and systemic vessels from ED in hypertension [43].



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