ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-PO844

RNA-Seq Analysis of Human Renal Allograft Biopsies Reveals Key Mediators of Interstitial Fibrosis/Tubular Atrophy

Session Information

  • Transplantation: Basic
    October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1801 Transplantation: Basic

Authors

  • McEvoy, Caitriona M., University Health Network, Toronto, Toronto, Ontario, Canada
  • Brennan, Eoin P., University College Dublin, Dublin, Ireland
  • Sadlier, Denise M., University College Dublin, Dublin, Ireland
  • Conlon, Peter J., Beaumont Hospital, Dublin 9, Co Dublin, Ireland
  • Konvalinka, Ana, University Health Network, University of Toronto, Toronto, Ontario, Canada
  • Godson, Catherine, The Conway Institute of Biomolecular and Biomedical, Belfield, Dublin, Ireland
Background

Interstitial Fibrosis/Tubular Atrophy(IFTA) is the final common pathway of most progressive renal diseases and is a potent predictor of renal outcome in both native and transplanted kidneys. IF/TA is a major cause of late allograft loss; however, our understanding of the molecular mechanisms underpinning this complex process remains incomplete.

Methods

We performed RNA-Seq gene expression profiling on renal tissue from transplanted patients undergoing a clinically indicated biopsy (n=21). IF/TA was determined from the renal biopsy report, and by quantitative morphometric analysis. Bioinformatic analysis was performed by DESeq2 to obtain differentially expressed (DE) genes. Ingenuity Pathway Analysis and MatInspector were employed to identify the key pathyways & transcription factors related to the dysregulated genes. NetworkAnalyst was used to generate a gene-protein interaction network.

Results

We identified 671 DE genes (381 upregulated, 236 downregulated; FDR<0.1) between severe and mild/moderate IF/TA in our cohort.
Pathway analysis revealed that B-Cell development, NRF2-mediated oxidative stress response & superoxide radical degredation comprise the top canonical pathways associated with the perturbed genes in our dataset. Pivotal upstream regulators are associated with lymphoid cell development (SPI1), proteasomal degradation (BACH1,LONP1) & regulation of antioxidant proteins (NFE2L2). In silico cell-type enrichment analysis reveals enhanced transcriptional signatures from CD19+ B-Cells, Dendritic cells & CD4+ T-cells in the expression profiles of patients with severe IF/TA.
DE genes were validated using external datasets prior to generating a gene-protein interaction network. Zero & first order interactions were examined. Significant gene modules detected in the networks relate to oxidative stress and mitochondrial function, T & B-Cell signalling, ECM-Receptor interaction, scaffolding proteins & chemokine signalling pathways.

Conclusion

Our dataset reveals novel molecular signatures and transcriptional regulators central to IF/TA using systems biology tools. These data underscore a prominent role of inflammation and oxidative stress in the development of IF/TA and reveal novel potential mediators of this process.