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Abstract: SA-OR92

Single-Nucleus Transcriptome Profiling of the Kidney Glomerulus Identifies Cell-Specific Responses in an Autoimmune Mouse Model of Membranous Nephropathy

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Huang, Ming, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Schnarre, Annabel, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Jauch-Speer, Saskia-L., Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Lu, Shun, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Liu, Shuya, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Sivayoganathan, Varshi, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Krebs, Christian F., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Huber, Tobias B., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Zahner, Gunther, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Tomas, Nicola M., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Background

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. However, the pathogenic mechanisms remain poorly understood due to a missing comprehensive characterization of cell-specific changes during disease progression.

Methods

We developed a novel pipeline involving the gentle enrichment of glomeruli followed by single-nucleus RNA-sequencing (snRNA-seq). We applied this technique to mice with experimental autoimmune THSD7A-associated MN at different time points.

Results

We generated a transcriptomic landscape involving 91,114 single-nuclei, with >95% deriving from glomerular cells, i.e. podocytes, mesangial cells and endothelial cells (ECs). This procedure provided a high-quality dataset with only minimal technical perturbations such as stress gene activation during the single cell dissociation process. Distinct changes in gene expression specific to podocytes were identified in MN model mice. A side-by-side comparison with other snRNA-seq datasets revealed both an MN-specific gene expression profile as well as transcriptomic alterations observed also in other glomerular nephropathies. Pathways enriched in MN model mice included regulation of focal adhesion, actin cytoskeleton, cell migration, and changes in kinase activities in podocytes. We further found increased infiltration of immune cells with disease progression and a cluster of proliferating/ repairing cells mainly consisting of mesangial cells and ECs in MN model mice. Interestingly, mesangial cells and ECs were identified to participate in modulation of leukocyte transendothelial migration, cytokine signaling, and cell-cell/cell-matrix interactions, indicating the involvement of various glomerular cell types in the pathogenesis of MN.

Conclusion

Our study identifies cellular pathways underlying podocyte injury in experimental MN and provides important novel molecular insights into the pathogenesis of MN.