Abstract: PO2449
Exploring the Presence of Endogenous Retroviruses in CKD
Session Information
- CKD: Inflammation, Endothelial Dysfunction, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Mulholland, Kelly Ann, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
- Dhillon, Poonam, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
- Hu, Hailong, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
- Liu, Hongbo, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
- Sheng, Xin, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
Group or Team Name
- Susztak Lab
Background
Chronic kidney disease (CKD) affects more than 1 in 7 US adults and is the fourth leading cause of death worldwide. However, the mechanism of CKD is poorly understood. Endogenous retroviruses (ERVs) are transposable elements (TEs) that have integrated into mammalian genomes millions of years ago, accounting for about 8% of the human genome. ERVs remain inactive in the genome due to mutations and deletions during evolution, however recent studies have found that reactivation of ERVs is possible and their increased expression has been identified in a variety of human diseases. Here, we examine ERVs in human and mouse kidneys and their potential role in CKD.
Methods
We performed RNA sequencing and collected clinical and histopathological data from 300 human kidney samples, both healthy and with varying degrees of CKD. We mapped the genomic landscape of TEs, including LINE, SINE and ERVs, using RepeatMasker and quantified their expression in healthy and diseased kidney tissues. Associations between ERV expression, gene expression and methylation level were analyzed. Similar analyses were performed on three kidney disease mouse models.
Results
We found increased expression of several ERV elements in diseased human kidney tissues. Using a linear regression model adjusted for 7 covariates, we identified 2,486 TEs whose expression showed a significant linear correlation with interstitial fibrosis. We also found that ERVs trigger a strong interferon response through the activation of cytosolic nucleic acid sensors such as RIG-I and STING. Furthermore, ERV expression was correlated with methylation level of overlapping methylation sites and we found that loss of cytosine methylation and epigenetic repression may have contributed to the increase in ERV level. We also identified several differentially expressed TEs between healthy and diseased kidney tissues in three kidney disease mouse models, many overlapping between models. An increase in expression of cytosolic nucleic acid sensors was also observed in mice. Furthermore, genetic deletion of RIG-I and STING ameliorated kidney inflammation and fibrosis in mouse disease models.
Conclusion
Our study provides the first comprehensive analysis of ERVs in the kidneys of both humans and mice and suggests the potential role of ERVs in kidney disease by aggravating immune response during disease progression.
Funding
- NIDDK Support