Kidney Week

Abstract: FR-OR39

Deciphering the Contribution of Macrophages to the Development of Focal Segmental Glomerulosclerosis

Session Information

• Glomerular Diseases: Mechanisms and More
  October 25, 2024 | Location: Room 1, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Sierra Gonzalez, Claudio, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Claudio Sierra Gonzalez, MS, MSc

• Nies, Jasper Friedrich, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Jasper Friedrich Nies, MD

• Trinsch, Bastian, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Bastian Trinsch

• Diefenhardt, Paul, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Paul Diefenhardt, MD

• Brinkkoetter, Paul T., University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Paul T. Brinkkoetter, MD

• Schermer, Bernhard, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Bernhard Schermer, MD

• Benzing, Thomas, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Thomas Benzing, MD, PhD, FASN

• Braehler, Sebastian, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany

Sebastian Braehler, MD

Background

FSGS is a severe kidney disease characterized by glomerular scarring, following podocyte injury. In its worst face, it leads to a significant kidney damage, resulting in nephrotic syndrome and end-stage kidney disease in both children and adults. A dysregulation of the immune system finds great acceptance as a driver of the disease.
To further analyze this, we make use of a murine model of a slowly progressing FSGS.

Methods

In a longitudinal fashion, we performed flow cytometry in order to phenotype the immune cell composition during disease progression. Among clinical parameters, like ACR and BUN, we assessed the histological damage via PAS and localized immune cells via IHC and IF. To further profile these immune cells, we performed single-nucleus RNA sequencing of isolated glomeruli.

Results

Based on our snRNAseq data, we detect an inflammatory and pro-fibrotic milieu with high activation of CX3CL1 as strong immune cell-recruiting factor. In accordance with this, flow cytometry data confirms an increase in mononuclear phagocyte infiltration and moreover, suggesting a functional shift in renal macrophages from a pro-inflammatory M1–like phenotype to a pro–fibrotic M2–like phenotype in diseased mice. Immunohistochemistry and immunofluorescence analyses underline this higher abundance of M2–like macrophages along disease progression. The lack of CX3CL1 in this model leads to an aggravated disease phenotype with a slightly shortened life span, increased BUN levels and an exacerbated M1-like to M2-like phenotypical alteration.

Conclusion

We identified mononuclear phagocytes to be the most prominent immune cells to infiltrate the kidney during FSGS progression, especially macrophage subpopulations displaying a pro-fibrotic transcriptomic signature. Furthermore, our findings suggest a strong association between the CX3CL1/CX3CR1 axis and the recruitment and polarization of renal macrophages. Notably, its absence has been shown to exacerbate the M1–like to M2–like phenotype shift, highlighting its potential regulatory role in macrophage polarization. Further research is necessary to elucidate the precise mechanism of how the CX3CL1/CX3CR1 axis might contribute to renal fibrosis and understanding this could pave the way for the development of targeted therapies.