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Abstract: TH-PO548

Deciphering the Contribution of Inflammatory Macrophages to Focal Segmental Glomerulosclerosis

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis


  • Nies, Jasper Friedrich, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Sierra Gonzalez, Claudio, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany
  • Diefenhardt, Paul, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Chen, He, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
  • Schermer, Bernhard, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Benzing, Thomas, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Kann, Martin, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Brinkkoetter, Paul T., Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Kurts, Christian, Universitatsklinikum Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Braehler, Sebastian, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Group or Team Name

  • Nephrolab Cologne.

Focal segmental glomerulosclerosis (FSGS) refers to a histologic pattern of glomerular injury that can result from heterogenous disease entitites, which in turn respond differently to therapeutic regimens. Causes for FSGS include immunological diseases that respond to immunosuppressive treatments. Modern biotechnological tools allow us to characterize diseases resulting in an FSGS pattern in detail with the prospect of providing pathophysiology-based precision medicine for the patients.


We used a genetic model (heterozygous compound mutations in Nphs2) that causes a slowly progressive FSGS phenotype with a strong intraglomerular immune cell infiltrate. In order to characterize these immune cells in depth and to identify glomerular communication patterns, we employed bulk and single nucleus RNA sequencing of glomerular isolates, flow cytometry, and immunohistochemistry.


We identified myeloid cells to be the most abundant immune cells in diseased glomeruli. A macrophage subpopulation with an M2-like, tissue-remodeling transcriptomic signature significantly expanded over time, which correlates with proteinuria. We confirmed such intraglomerular infiltration of macrophages by immunohistochemistry, and detected macrophages in the tubulointerstitium at a later stage of the disease. snRNAseq-based ligand-receptor-target gene network analysis indicated progressively altered signaling between glomerular cells resulting in a pro-fibrotic inflammatory milieu characterized by strong signaling activity of the TGFb-superfamily and upregulation of CC-chemokines and matrix metalloproteinases. Intriguingly, fractalkine (CX3CL1), a macrophage recruiting chemokine, was strongly upregulated at an early stage of the disease. Immuno-staining localized fractalkine to glomerular endothelial cells while flow cytometry showed significant upregulation of its receptor CX3CR1 on macrophages.


In this model, a mutation in a slit-diaphragm protein results in a glomerular fibro-inflammatory phenotype with strong macrophage infiltration that may be linked to fractalkine. Based on these results, our project might provide the rationale for new therapeutic approaches in FSGS.


  • Government Support – Non-U.S.