Lubczańska, Maria A. (2013) The human vascular vitamin D hormonal system - expression and regulation. PhD thesis, University of Warwick.

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Abstract

Background: Patients suffering from chronic kidney disease (CKD) are at high risk
of cardiovascular related premature death. In addition, traditional strategies for
preventing cardiovascular disease (CVD) in patients with normal kidney function are
less successful in patients with CKD. Vascular calcification (VC) and cardiac
hypertrophy are common consequences. Recent evidence suggests that activation of
the vitamin D receptor (VDR) is protective and is associated with significantly better
survival in end stage renal disease (ESRD).
Vascular smooth muscle cells (VSMCs) play a key role in the process of CKDrelated
arteriopathy and are capable of phenotype transformation into
chondro/osteoblast-like cells, which promotes the deleterious vascular effects,
including calcification.
Although the kidney is the main site of 1,25(OH)2D synthesis, some other non-renal
tissues also express, VDR, 25-hydroxyvitamin D 1α-hydroxyalse (1α-OHase) an
enzyme responsible for the synthesis of 1,25(OH)2D, and 1,25(OH)2D 24-
hydroxylase (24-OHase), an enzyme responsible for the catabolism of 1,25(OH)2D.
Extra-renal 1,25(OH)2D can affect a multitude of pathways in an autocrine/paracrine
way, without the involvement of the endocrine system.
Aims: This project aimed to investigate the role of autocrine vitamin D signalling in
human VSMCs using both arterial tissue from ESRD and non-ESRD patients and
primary cultures of human aortic smooth muscle cells (HAoSMCs). Specific aims
were to characterise the expression and functionality of vitamin D system in
vasculature as well as to examine the effect of classical regulators of the endocrine
vitamin D system – 1,25(OH)2D3, calcium, phosphate, TNF-α and other interleukins,
as well as novel factors such as FGF-23 and Klotho, on the local vitamin D
metabolism in arteries.
Results: We have demonstrated the presence of VDR, 1-OHase and 24-OHase in
human kidney, artery and HAoSMCs. To our knowledge, we are the first to
demonstrate the presence of 24-OHase in arteries. Our data suggested diminished
expression of VDR mRNA and protein, with significantly decreased levels of 1α-
OHase protein expression in CKD patients. Further crucial finding was the apparent
increase of 24-OHase protein in CKD arteries suggested higher local vitamin D
catabolism in CKD. In order to establish which factors regulate expression of 1α-
OHase, 24-OHase and VDR in HAoSMCs, further studies were undertaken. Results
confirmed that treatment with high calcium, phosphate, TNF-α, INF-γ, IL-6, IL-17A,
FGF-23 or Klotho modulated VDR protein expression, which had further effect on
expression of 1α-OHase and 24-OHase mRNA and protein.
Conclusions: The results suggest that altered mineral and inflammatory
environment, characteristic to CKD may favour local 1,25(OH)2D3 catabolism,
potentially driving transdifferentiation of VSMCs, leading to VC. Vascular VDR
activation, in particular through local metabolic activation, is crucial for vascular
health, especially, under stress conditions. Local inducers and inhibitors of vascular
vitamin D system have been determined, however further examination is required for
potential application in future treatment of CKD related VC.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Library of Congress Subject Headings (LCSH):	Chronic renal failure -- Treatment -- Research, Vitamin D -- Metabolism, Vascular smooth muscle, Blood-vessels -- Physiology
Official Date:	May 2013
Dates:	Date Event May 2013 Submitted
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Zehnder, Daniel; Bland, Rosemary
Sponsors:	Warwick Medical School
Extent:	xx, 288 leaves : charts.
Language:	eng

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