Research Paper Volume 12, Issue 9 pp 7830—7847
Intrarenal arteriosclerosis and telomere attrition associate with dysregulation of the cholesterol pathway
- 1 Department of Microbiology and Immunology, KU Leuven – University of Leuven, Leuven, Belgium
- 2 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
- 3 Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
- 4 Department of Imaging and Pathology, KU Leuven – University of Leuven, Leuven, Belgium
- 5 Department of Pathology, University Hospitals Leuven, Leuven, Belgium
- 6 Department of Public Health and Primary Care, KU Leuven – University of Leuven, Leuven, Belgium
received: December 12, 2019 ; accepted: March 30, 2020 ; published: April 30, 2020 ;https://doi.org/10.18632/aging.103098
How to Cite
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.
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.