title: Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23.
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.
  
  
  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.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Room 120, 41 Ave Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lim
authors.forename: Tzong-Shi
authors.initials: TS
authors.lastname: Lu
authors.forename: Guerman
authors.initials: G
authors.lastname: Molostvov
authors.forename: Christina
authors.initials: C
authors.lastname: Lee
authors.forename: F T
authors.initials: FT
authors.lastname: Lam
authors.forename: Daniel
authors.initials: D
authors.lastname: Zehnder
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Hsiao
mesh_terms: D001011:Aorta / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000096:biosynthesis / Q000172:deficiency*; D006801:Humans; D000090265:Klotho Proteins; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D061205:Vascular Calcification / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; D018167:Receptors, Calcitriol; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C000717427:FGF23 protein, human; C493709:RUNX2 protein, human