Abstract: FR-OR38
Endogenous Retroviruses Contribute to Kidney Fibrosis Development by Triggering the Innate Immune Response
Session Information
- Diabetic Kidney Disease: From Single Cell to Outcomes
November 04, 2022 | Location: W240, Orange County Convention Center‚ West Building
Abstract Time: 05:33 PM - 05:42 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Dhillon, Poonam, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Mulholland, Kelly A., University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Hu, Hailong, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Sheng, Xin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Abedini, Amin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Vassalotti, Allison, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Wu, Junnan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Group or Team Name
- Susztak Lab
Background
Inflammation is a common feature of diabetic kidney disease (DKD); however, underlying mechanisms triggering inflammation remain poorly understood. Endogenous retroviruses (ERVs) are transposable elements (TEs) that were fixed in the genome by cumulative exogenous retroviral infection over millions of years. ERVs constitute 10% of the human and mouse genome. ERVs are dynamically silenced in the genome by cytosine methylation or other repressive epigenetic modifications. The aim of this study was to characterize ERV expression and to understand its role in kidney disease development.
Methods
We performed RNA-seq and genome-wide methylation analysis on 485 human kidney samples and mouse kidney fibrosis models induced by folic acid injection (FAN) or unilateral ureteral obstruction (UUO) and quantified TEs using RepeatMasker and full-length ERVs by HERVQuant. Mouse models with kidney tubule-specific deletion of DNA methyltransferase 1 (DNMT1) and nucleotide sensors (STING and RIG-I) were generated. For in-vitro experiments, primary cultures of mouse kidney tubule cells were analyzed.
Results
Our analysis identified 1925 TEs and 74 ERVs levels that were increased and correlated with kidney disease severity in patients. We detected increased expression of 560 TEs in UUO and 130 TEs in FAN mice kidneys. The strong correlation between ERVs and cytosolic demethylation suggested that epigenetic derepression likely contributes to increased TE/ERV levels in diseased kidneys. Kidney-specific genetic deletion or pharmacological inhibition of DNMT1 resulted in increased TE/ERV levels leading to renal inflammation and fibrosis. The ectopic expression of ERV in cultured kidney tubule cells triggered the activation of cytosolic nucleotide sensors such as RIG-I, MDA5, and STING and the expression of IFN-stimulated genes (ISGs). TEs/ERVs expression in human and mice kidney tissue samples correlated with RIG-I/STING pathway gene expression and with kidney immune cell fractions. Genetic deletion of RIG-I or STING or treatment mice with reverse transcriptase inhibitor ameliorated kidney fibroinflammation.
Conclusion
Epigenetic derepression mediated increased ERV levels contribute to the sterile inflammation in DKD by activating the cytosolic nucleotide sensing pathways (RIG-I/STING).
Funding
- NIDDK Support