Abstract
AbstractInflammation is a common feature of all forms of chronic kidney disease; however, the underlying mechanism remains poorly understood. Evolutionarily inherited endogenous retroviruses (ERVs) have the potential to trigger an immune reaction. Comprehensive RNA-sequencing of control and diseased kidneys from human and mouse disease models indicated higher expression of transposable elements (TEs) and ERVs in diseased kidneys. Loss of cytosine methylation causing epigenetic derepression likely contributes to an increase in ERV levels. Genetic deletion/pharmacological inhibition of DNA methyltransferase 1 (DNMT1) induces ERV expression. In cultured kidney tubule cells, ERVs elicit the activation of cytosolic nucleotide sensors such as RIG-I, MDA5, and STING. ERVs expressions in kidney tubules trigger RIG-I/STING, and cytokine expression, and correlate with the presence of immune cells. Genetic deletion of RIG-I or STING or treatment with reverse transcriptase inhibitor ameliorates kidney fibroinflammation. Our data indicate an important role of epigenetic derepression-induced ERV activation triggering renal fibroinflammation.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference72 articles.
1. Levin, A. et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 390, 1888–1917 (2017).
2. C.D.C. Chronic Kidney Disease in the United States (US Department of Health and Human Services, C. & Prevention, f.D.C.a., 2021).
3. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
4. Lee, A., Nolan, A., Watson, J. & Tristem, M. Identification of an ancient endogenous retrovirus, predating the divergence of the placental mammals. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20120503 (2013).
5. Nelson, P. N. et al. Demystified. Human endogenous retroviruses. Mol. Pathol. 56, 11–18 (2003).
Cited by
6 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献