Increased Levels of Endogenous Retroviruses Promote Cyst Growth in ADPKD

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Background: Endogenous retroviruses (ERVs) are the long terminal repeats (LTRs)-retrotransposons, which occupy 8% of the human genome and 10% of the mouse genome. Acquired mutations in ERV sequences during evolution made them inactive, whereas ERVs can be activated by the weakening of epigenetic silencing mechanisms to trigger an immune reaction. However, the role of ERVs in the ADPKD remains unknown. Methods: To investigate the role of ERVs in ADPKD, we perform bioinformatic analysis to determine the expression of ERVs in Pkd1 mutant kidneys, and examine the changes of the expression of ERVs by western blot, qRT-PCR, IHC staining (IHC), ChIP, methylation-specific PCR (MSP) in ADPKD and Pkd1 mutant mouse kidneys. We test the effect of a reverse transcriptase inhibitor which inhibits the reverse transcription of ERVs and an inhibitor of Tet1 in delaying cyst growth in ADPKD mice. Results: We found that HERVK exhibited the highest expression among the HERV class in human ADPKD kidneys. The proteins of HERVK and its downstream targets, including RIG-I, MDA5, STING, pSTING, were increased in cyst-ling epithelial cells in ADPKD kidneys. Overexpression of HERVK and transfection of the total dsRNAs isolated from Pkd1RC/RC kidneys in Pkd1 mutant cells activated the RIG-I/MDA5 and RIG-I/STING pathways, increased the expression of type I IFN response genes and the activation of PKD associated signaling pathways (AKT, S6, Erk). We also found that dsRNAs bound to RIG-I, which was decreased in RIG-I knockdown Pkd1 mutant cells. The expression of ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) was also increased in cyst-ling epithelial cells in ADPKD and Pkd1 mutant kidneys, which could demethylate HERVK in ADPKD kidneys and also demethylate the common ERVs fragments, including MuLV, RLTR4, MMTV, LTRIS, GypLTR3A, MuRRS4, and LTR45, in Pkd1RC/RC kidneys. Treatment with Tet1 inhibitor and reverse transcriptase inhibitor delays cyst growth in Pkd1 mutant mice. Conclusion: The expression of ERVs is increased in Pkd1 mutant mouse and ADPKD kidneys, possibly through Tet1 mediated DNA demethylation, leading to the activation of RIG-I/MDA5 and RIG-I/STING pathways and the increase of cytokine expression to promote cyst growth in ADPKD. Inhibition of the reverse transcription of ERVs with reverse transcriptase inhibitor and targeting Tet1 are novel therapeutic strategies for ADPKD.

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