title: CDKN2A/p16INK4aexpression is associated with vascular progeria in chronic kidney disease.
abstract: Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a,SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression ofCDKN2A/p16INK4aassociated with vascular progeria in CKD, independently of chronological age. The arterial expression ofCDKN2A/p16INK4awas significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation betweenCDKN2A/p16INK4aand media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression ofCDKN2A/p16INK4a,RUNX2andMGPwere observed in arteries with severe media calcification. The number ofp16INK4aand SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed betweenCDKN2A/p16INK4aexpression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence.
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Stenvinkel
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Luttropp
authors.affiliation: Wolfson Wohl Translational Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Dagmara
authors.initials: D
authors.lastname: McGuinness
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Witasp
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Abdul Rashid
authors.initials: AR
authors.lastname: Qureshi
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.|Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Nordfors
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Division of Radiology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Stockholm, Sweden.
authors.forename: Jonaz
authors.initials: J
authors.lastname: Ripsweden
authors.affiliation: Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wennberg
authors.affiliation: Pathology, Drug Safety and Metabolism, AstraZeneca, Mölndal, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Söderberg
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bárány
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.affiliation: Wolfson Wohl Translational Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Shiels
mesh_terms: D000328:Adult; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011371:Progeria / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D014652:Vascular Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D016326:Extracellular Matrix Proteins; D000097568:Matrix Gla Protein; C000614131:CDKN2A protein, human; C493709:RUNX2 protein, human
keywords: chronic kidney disease; p16; vascular calcification; vascular senescence; vitamin