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Role of Klotho in the development of vascular calcification in patients with chronic kidney disease (CKD)
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Lim, Kenneth Jia-En (2012) Role of Klotho in the development of vascular calcification in patients with chronic kidney disease (CKD). PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2583189~S1
Abstract
Background: Cardiovascular disease is the leading cause of mortality in patients
with Chronic Kidney Disease (CKD). Vascular calcification is a significant contributor
to cardiovascular mortality in CKD. Klotho is a 130kDa transmembrane protein with
cardiovasculo-protective properties and also functions as a co-factor for the
phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in
CKD despite progression of accelerated vascular calcification (VC). There are
currently conflicting data on whether FGF-23 may exhibit direct vasculo-protective
effects in CKD.
Methods and results: In this study, we describe for the first time endogenous
Klotho expression in human arteries and human aortic smooth muscle cells (HASMCs).
We show that CKD is a state of vascular Klotho deficiency promoted by
chronic circulating stress factors, including pro-inflammatory, uremic and disordered
metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown
potentiated the development of accelerated calcification through a Runx2 and
myocardin-SRF dependent pathway. Klotho knockdown studies further revealed
that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23
mediated cellular activation of p-ERK, p-AKT and cellular proliferative effects, which
were abrogated following Klotho knockdown. We next showed that vascular Klotho
deficiency driven by pro-calcific stressors could be restored by vitamin D receptor
(VDR) activators, in vitro and further confirmed using human arterial organ cultures
from CKD patients, in vivo. Furthermore, restoration of Klotho by vitamin D receptor
(VDR) activators conferred HA-SMCs FGF-23 responsive and unmasked its anticalcific
effects.
Conclusions: Chronic metabolic stress factors found in CKD promote vascular
Klotho deficiency. Mechanistic studies revealed a bi-functional role for local vascular Klotho, first as an endogenous inhibitor of VC and second, as a co-factor required
for vascular FGF-23 signalling. Furthermore, VDR activators can restore Klotho
expression and unmask FGF-23 anti-calcific effects.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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Library of Congress Subject Headings (LCSH): | Cardiovascular system -- Diseases, Kidneys -- Diseases, Arteries -- Calcification, Membrane proteins | ||||
Official Date: | July 2012 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Hsiao, Li-Li ; Zehnder, Daniel | ||||
Extent: | x, 240, [39] leaves : ill., charts | ||||
Language: | eng | ||||
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