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

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.

The contribution of transposable elements and endogenous retroviruses to renal fibroinflammation is currently unknown. Here, the authors comprehensively profile the expression of transposable elements and endogenous retroviruses (ERVs) in kidneys of patients and mouse disease models and find expression of ERVs in diseased kidneys activate cytosolic nucleotide sensors contributing to cytokine release and renal fibroinflammation.