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Kidney Week

Abstract: PO0639

Downregulated Endothelial JMJD3 Accelerates Neointimal Hyperplasia of Arteriovenous Fistula in CKD

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Feng, Shaozhen, Baylor College of Medicine, Houston, Texas, United States
  • Guo, Qunying, Baylor College of Medicine, Houston, Texas, United States
  • Peden, Eric K., Houston Methodist Hospital DeBakey Cardiology Associates, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
  • Truong, Luan D., Houston Methodist Hospital, Houston, Texas, United States
  • Cheng, Jizhong, Baylor College of Medicine, Houston, Texas, United States
Background

Epigenetic changes are involved in vascular remodeling. The histone demethylase, Jmjd3, is a transcriptional co-activator that promotes endothelial regeneration. Despite the importance of Jmjd3 in maintaining endothelial function, its role in neointima formation in AVF remains unknown.

Methods

Mice with JMJD3 specific knockout (KO) in ECs was generated. CKD and AVF models were created in Wild type and Jmjd3 EC-specific KO mice. Evans blue, immunostaining assays were used to characterize JMJD3 expression and vascular pathology. Mouse primary ECs and VSMCs were isolated to study the signaling pathways that regulate Jmjd3 expression and endothelial mesenchymal transition (EndMT). The changes found in mouse AVFs were assessed in AVFs from ESRD patients.

Results

JMJD3 expression was downregulated in endothelium of CKD mice. Specific KO of JMJD3 in EC stimulated endothelial barrier dysfunction, EndMT, and inflammatory cells infiltration in AVFs. There were more VSMC proliferation and collagen deposition in AVFs created in Jjmd3 KO mice vs. that of in WT mice. Specific KO of JMJD3 in EC accelerated neointimal hyperplasia of AVF in CKD mice. In vitro, inhibition of JMJD3 activity reduced EC proliferation and migration. Suppression of Jmjd3 enhanced the level of histone H3K27me3 promoting its binding to the promoter of EC markers (VE-cadherin and eNOS). These responses resulted in EnMT and VSMC proliferation. Moreover, the expression of JMJD3 is reduced through TGFβ1/Hes1 signaling pathway. In AVFs from ESRD patients, the decreased expression of JMJD3 in ECs was associated with endothelial dysfunction, EndMT, and ECM deposition plus neointimal hyperplasia. Remarkably, endothelial expression of Hes1 in AVFs from ESRD patients was correlated with the decreased JMJD3 level.

Conclusion

These findings demonstrate that TGFβ1-Hes1-JMJD3 signaling exist in ECs which epigenetically regulates EC differentiation and barrier function leading to neointimal hyperplasia of AVF in CKD.

Funding

  • NIDDK Support