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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589838 |
| Date | January 2013 |
| Creators | Lubczańska, Maria A. |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/58451/ |
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