Increased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development

Poonam Dhillon, Kelly Ann Mulholland, Hailong Hu, Jihwan Park, Xin Sheng, Amin Abedini, Hongbo Liu, Allison Vassalotti, Junnan Wu and Katalin Susztak ()
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Poonam Dhillon: University of Pennsylvania, Perelman School of Medicine
Kelly Ann Mulholland: University of Pennsylvania, Perelman School of Medicine
Hailong Hu: University of Pennsylvania, Perelman School of Medicine
Jihwan Park: University of Pennsylvania, Perelman School of Medicine
Xin Sheng: University of Pennsylvania, Perelman School of Medicine
Amin Abedini: University of Pennsylvania, Perelman School of Medicine
Hongbo Liu: University of Pennsylvania, Perelman School of Medicine
Allison Vassalotti: University of Pennsylvania, Perelman School of Medicine
Junnan Wu: University of Pennsylvania, Perelman School of Medicine
Katalin Susztak: University of Pennsylvania, Perelman School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Inflammation 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.

Date: 2023
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DOI: 10.1038/s41467-023-36212-w

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