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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560387 |
| Date | January 2012 |
| Creators | Lim, Kenneth Jia-En |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/50202/ |
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