title: Arterial klotho expression and FGF23 effects on vascular calcification and function.
abstract: Recent studies support a role for FGF23 and its co-receptor Klotho in cardiovascular pathology, yet the underlying mechanisms remain largely elusive. Herein, we analyzed the expression of Klotho in mouse arteries and generated a novel mouse model harboring a vascular smooth muscle cell specific deletion of Klotho (Sm22-KL(-/-) ). Arterial Klotho expression was detected at very low levels with quantitative real-time PCR; Klotho protein levels were undetectable by immunohistochemistry and Western blot. There was no difference in arterial Klotho between Sm22-KL(-/-) and wild-type mice, as well as no changes in serum markers of mineral metabolism. Intravenous delivery of FGF23 elicited a rise in renal (0.005; p<0.01) but not arterial Egr-1 expression, a marker of Klotho-dependent FGF23 signaling. Further, the impact of FGF23 on vascular calcification and endothelial response was evaluated in bovine vascular smooth muscle cells (bVSMC) and in a murine ex vivo model of endothelial function, respectively. FGF23 treatment (0.125-2 ng/mL) did not modify calcification in bVSMCs or dilatory, contractile and structural properties in mice arterial specimen ex vivo. Collectively, these results demonstrate that FGF23-Klotho signaling is absent in mouse arteries and that the vascular response was unaffected by FGF23 treatment. Thus, our data do not support Klotho-mediated FGF23 effects in the vasculature although confirmative studies in humans are warranted.
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Lindberg
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.forename: Risul
authors.initials: R
authors.lastname: Amin
authors.forename: Arvind
authors.initials: A
authors.lastname: Ponnusamy
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Taylor
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Ann
authors.initials: A
authors.lastname: Canfield
authors.forename: Karolina
authors.initials: K
authors.lastname: Kublickiene
authors.forename: Tobias E
authors.initials: TE
authors.lastname: Larsson
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects*; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013997:Time Factors
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins