Lim, Kenneth Jia-En, Lu, T. -S., Molostvov, Guerman, Lee, C., Lam, F. T., Zehnder, Daniel and Hsiao, L. -L.. (2012) Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation, Vol.125 (No.18). pp. 2243-2255. ISSN 0009-7322

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Abstract

Background-Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective 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. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor- 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 procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects. Conclusions-Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects. © 2012 American Heart Association, Inc.

Item Type:	Journal Article
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Circulation
Publisher:	American Heart Association
ISSN:	0009-7322
Date:	8 May 2012
Volume:	Vol.125
Number:	No.18
Page Range:	pp. 2243-2255
Identification Number:	10.1161/CIRCULATIONAHA.111.053405
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/50292

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