title: Early chronic kidney disease-mineral bone disorder stimulates vascular calcification.
abstract: The chronic kidney disease-mineral and bone disorder (CKD-MBD) syndrome is an extremely important complication of kidney diseases. Here we tested whether CKD-MBD causes vascular calcification in early kidney failure by developing a mouse model of early CKD in a background of atherosclerosis-stimulated arterial calcification. CKD equivalent in glomerular filtration reduction to human CKD stage 2 stimulated early vascular calcification and inhibited the tissue expression of α-klotho (klotho) in the aorta. In addition, osteoblast transition in the aorta was stimulated by early CKD as shown by the expression of the critical transcription factor Runx2. The ligand associated with the klotho-fibroblast growth factor receptor complex, FGF23, was found to be expressed in the vascular media of sham-operated mice. Its expression was decreased in early CKD. Increased circulating levels of the osteocyte-secreted proteins, FGF23, and sclerostin may have been related to increased circulating klotho levels. Finally, we observed low-turnover bone disease with a reduction in bone formation rates more than bone resorption. Thus, the CKD-MBD, characterized by cardiovascular risk factors, vascular calcification, increased circulating klotho, FGF23 and sclerostin levels, and low-turnover renal osteodystrophy, was established in early CKD. Early CKD caused a reduction of vascular klotho, stimulated vascular osteoblastic transition, increased osteocytic secreted proteins, and inhibited skeletal modeling producing the CKD-MBD.
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Washington University, St Louis, Missouri, USA.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Washington University, St Louis, Missouri, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Ginsberg
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Washington University, St Louis, Missouri, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Sugatani
authors.affiliation: Division of Nephrology, Department of Medicine, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Monier-Faugere
authors.affiliation: Division of Nephrology, Department of Medicine, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Malluche
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Washington University, St Louis, Missouri, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D016723:Bone Remodeling; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000097:blood; D005966:Glucuronidase / Q000097:blood*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D061205:Vascular Calcification
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D011506:Proteins; C013247:sclerotin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins