ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

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

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO821

Network-Based Assessment of Minimal Change Disease Identifies Glomerular IL7 Pathway Activation as Potential Mechanism for Biomarker Discovery and Drug Testing

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Lillefosse, Bjørnar Sandnes, University of Bergen, Bergen, Norway
  • Strauss, Philipp, University of Bergen, Bergen, Norway
  • Eikrem, Oystein, University of Bergen, Bergen, Norway
  • Delaleu, Nicolas, Institute of Oncology Research (IOR), Bellinzona, Switzerland
  • Vikse, Bjorn Egil, University of Bergen, Bergen, Norway
  • Debiec, Hanna, INSERM UMRS 1155, Paris, France
  • Ronco, Pierre M., INSERM UMRS 1155, Paris, France
  • Leh, Sabine, Haukeland University Hospital, Bergen, Norway
  • Marti, Hans-Peter, University of Bergen, Bergen, Norway

Group or Team Name

  • Renal Research Group Bergen
Background

Minimal change disease (MCD) is a major cause of the nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, our study aim was to determine the glomerular transcriptome of MCD to serve as base for biomarker discovery and drug target identification. Respective animal work showed podocyte injury induced by IL7/IL7R signaling (Zhai S, BBRC, 2018).

Methods

Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as two reference groups. Glomerular RNA for 75 base-pair, paired-end RNA-seq was obtained via laser capture microdissection from archival FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources.

Results

Compared to normal glomeruli, glomeruli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation, and by depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominantly in MDC and were significantly less pronounced in MN.

Conclusion

Our results demonstrate that archival renal biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney diseases. We provide a data-driven rationale to experimentally address the MCD-specific features as biomarkers and as novel drug targets. In this context, inhibiting the activation of IL7 pathway is particularly promising.