Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to FGF-23
Background—Klotho is known to function 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 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 (HA-SMCs). 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 VDR activators conferred HA-SMCs FGF-23 responsive and unmasked potential anti-calcific 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 signaling. Furthermore, VDR activators can restore Klotho expression and unmask FGF-23 anti-calcific effects.
- Received July 3, 2011.
- Accepted March 9, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited