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

Peter Stenvinkel,Martin Schalling,Hannes Olauson,Abdul Rashid Qureshi,Anna Witasp,Dagmara Mcguinness,Peter Bárány,Karin Luttropp,Lars Wennberg,Jonaz Ripsweden,Magnus Söderberg,Annika Wernerson,Louise Nordfors,Paul G Shiels

doi:10.18632/aging.101173

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.

Highlights

When chronic kidney disease (CKD) progresses to endstage renal disease (ESRD), the risk of cardiovascular mortality increases exponentially [1] and occur at a much younger age [2]
We report that the arterial CDKN2A/p16INK4a expression associate with cardiovascular disease (CVD) as well as degree of vascular calcification (VC) in ESRD
The p16INK4a expression was localised to the cell nucleus and involved more cells in severe VC

Summary

INTRODUCTION

When chronic kidney disease (CKD) progresses to endstage renal disease (ESRD), the risk of cardiovascular mortality increases exponentially [1] and occur at a much younger age [2]. This suggests that CKD could be used as a clinical model to study premature vascular ageing [3, 4]. I.e. medial vascular calcification (VC), is a distinct feature in CKD that predicts poor outcome [5] Osteogenic factors, such www.aging-us.com as matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2), are part of the calcification process. We related degree of VC to the number of p16INK4a and senescence associated β−galactosidase (SA-β−Gal) positive cells

RESULTS

DISCUSSION

MATERIALS AND METHODS