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Research Paper|Volume 9, Issue 2|pp 494—507

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Peter Stenvinkel1, Karin Luttropp2, Dagmara McGuinness3, Anna Witasp1, Abdul Rashid Qureshi1, Annika Wernerson1, Louise Nordfors1,2, Martin Schalling2, Jonaz Ripsweden4, Lars Wennberg5, Magnus Söderberg6, Peter Bárány1, Hannes Olauson1, Paul G Shiels3
  • 1Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
  • 2Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  • 3Wolfson Wohl Translational Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
  • 4Division of Radiology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • 5Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Stockholm, Sweden
  • 6Pathology, Drug Safety and Metabolism, AstraZeneca, Mölndal, Sweden
Received: November 13, 2016Accepted: February 3, 2017Published: February 9, 2017
https://doi.org/10.18632/aging.101173

Copyright: © 2017 Stenvinkel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and 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 of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence.