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Kidney Week

Abstract: FR-PO1127

DNA Methylation Profiling Reveals Epigenetic Differences Before and After Acute Rejection-Induced Allograft Dysfunction

Session Information

  • Transplantation: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Zhu, Chaohong, Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
  • Jiang, Hong, Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
  • Chen, Jianghua, Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Background

The incidence of acute rejection (AR) has declined to <15% in the first year after renal transplantation but remains a risk factor for allograft nephropathy and determination of allograft fate. DNA methylation regulates gene expression and persists after removal of the stimulus. Here, we analyzed dynamic changes in the methylation landscapebefore and after AR-induced allograft dysfunction.

Methods

In this two-cohort study, we followed-up with identical patients who successively experienced end-stage renal disease, renal transplantation with allograft function or dysfunction, and final hemodialysis. Peripheral blood mononuclear cells from the same patients were collected at different time points and used for mircoarray analysis of changes in DNA-methylation status.

Results

In contrast to the allograft-stable cohort, AR accelerated changes in DNA-methylation patterns. Pathway analysis revealed that hypermethylated areas associated with genes were related to T cell receptor, nuclear factor-kappa B, and mammalian target of rapamycin signaling in the AR-induced allograft-dysfunction group, which differed from pathways associated with hypomethylated areas. Moreover, AR altered the methylation status of genes related to epigenetic modification, and in a mouse model of AR, the DNA-methyltransferase inhibitor decitabine ameliorated renal allograft-related inflammatory injuries by enhancing regulatory T cell activities through inhibiting DNMT1 and suppressing T helper 1/2/17.

Conclusion

These results revealed that AR after renal transplantation reshapes the DNA-methylation landscape, with hypermethylated genes associated with AR, and suggested inhibition of DNA methylation as a potential therapeutic approach for AR after organ transplantation to improve allograft survival.

Funding

  • Government Support - Non-U.S.