Role of Klotho in the development of vascular calcification in patients with chronic kidney disease (CKD)
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.Full text not available from this repository.
Official URL: http://webcat.warwick.ac.uk/record=b2583189~S1
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 or Dissertation (PhD)|
|Subjects:||Q Science > QP Physiology
R Medicine > RC Internal medicine
|Library of Congress Subject Headings (LCSH):||Cardiovascular system -- Diseases, Kidneys -- Diseases, Arteries -- Calcification, Membrane proteins|
|Institution:||University of Warwick|
|Theses Department:||Warwick Medical School|
|Supervisor(s)/Advisor:||Hsiao, Li-Li ; Zehnder, Daniel|
|Extent:||x, 240,  leaves : ill., charts|
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