Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/31233
Title: Intrarenal arteriosclerosis and telomere attrition associate with dysregulation of the cholesterol pathway
Authors: De Vusser, Katrien
WINCKELMANS, Ellen 
MARTENS, Dries 
Lerut, Evelyne
Kuypers, Dirk
NAWROT, Tim 
Naesens, Maarten
Issue Date: 2020
Publisher: IMPACT JOURNALS LLC
Source: Aging-US, 12 (9) , p. 7830 -7847
Abstract: Background: Recently, we demonstrated that arteriosclerosis in the smaller intrarenal arteries is associated with shorter telomere length, independently of history of cardiovascular events and calendar age. This suggests that intrarenal arteriosclerosis reflects replicative senescence, although the underlying molecular alterations remain unclear. Results: Shorter intrarenal telomere length associated significantly with the presence of renal arteriosclerosis (T/S ratio 0.91±0.15 vs. 1.20±0.23 with vs. without arteriosclerosis, p=0.007, test cohort; T/S ratio 0.98 ±0.26 vs. 1.03 ±0.18 with vs. without arteriosclerosis, p=0.02, validation cohort). The presence versus absence of intrarenal arteriosclerosis was associated with differential expression of 1472 transcripts. Pathway analysis revealed enrichment of molecules involved in the superpathway of cholesterol biosynthesis as the most significant. The differential expression of these genes was confirmed in the independent validation cohort. Furthermore, the specific mRNA expression of the molecules in the superpathway of cholesterol biosynthesis associated significantly with intrarenal telomere length, and with history of cardiovascular events. Interpretation: Our study illustrates that the superpathway of cholesterol biosynthesis interacts with the previously published association between shorter telomere length and arteriosclerosis. Methods: This study included a test cohort of 40 consecutive kidney donors (calendar age 48.0 ± 15), with biopsies obtained prior to transplantation. Intrarenal leucocyte telomere length content was assessed using quantitative RT-PCR. Whole genome microarray mRNA expression analysis was performed using Affymetrix Gene 2.0 ST arrays. We investigated the associations between mRNA gene expression, telomere length as marker of replicative senescence, and intrarenal arteriosclerosis (Banff "cv" score = vascular fibrous intimal thickening = intimal hyperplasia) using adjusted multiple regression models. For biological interpretation and pathway overrepresentation analysis, we used Ingenuity Pathway Analysis. The significant pathways and genes were validated in an independent validation cohort of 173 kidney biopsies obtained prior to transplantation.
Keywords: aging;senescence;telomeres;cholesterol pathway;arteriosclerosis
Document URI: http://hdl.handle.net/1942/31233
ISSN: 1945-4589
DOI: 10.18632/aging.103098
ISI #: 000533150800018
Rights: Copyright © 2020 De Vusser 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.
Category: A1
Type: Journal Contribution
Validations: ecoom 2021
Appears in Collections:Research publications

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