Kidney Week

Abstract: FR-OR43

Single-Cell Metabolic Profiling of Kidney T Cells Reveals Key Importance of Glycolysis in Crescentic Glomerulonephritis

Session Information

• Glomerular Diseases: Mechanisms and More
  October 25, 2024 | Location: Room 1, Convention Center
  Abstract Time: 05:30 PM - 05:40 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Nies, Jasper Friedrich, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Jasper Friedrich Nies, MD

• Trinsch, Bastian, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Bastian Trinsch

• Sierra Gonzalez, Claudio, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Claudio Sierra Gonzalez, MS, MSc

• Diefenhardt, Paul, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Paul Diefenhardt, MD

• Eckey, Tobias, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Tobias Eckey, MS

• Puetz, David L., Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

David L. Puetz

• Schermer, Bernhard, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Bernhard Schermer, MD

• Benzing, Thomas, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Thomas Benzing, MD, PhD, FASN

• Corrado, Mauro, University of Cologne, Faculty of Mathematics and Natural Sciences, Institute for Genetics, Cologne, Germany, Cologne, Nordrhein-Westfalen, Germany

Mauro Corrado, PhD

• Brinkkoetter, Paul T., Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Paul T. Brinkkoetter, MD

• Braehler, Sebastian, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Sebastian Braehler, MD

Group or Team Name

• Braehler Group.

Background

Crescentic glomerulonephritis (cGN) is a devastating, T cell mediated autoimmune disease. The supply with various metabolites and their utilization is crucial for T cell function and activation. How employment of oxidative phosphorylation and glycolysis govern T cell fate and function during cGN is unclear but of central importance to expand our understanding of the disease’s pathogenesis. These insights could open up new avenues for therapeutic intervention.

Methods

We use the model of nephrotoxic nephritis (NTN) to investigate T cell metabolism in homeostasis and disease. Due to the scarcity of T cells in mouse kidneys, we use single-cell-based methods including innovative immunometabolic assays in flow cytometry (SCENITH) and mass spectrometry (scMEP) as well as the analysis of scRNAseq datasets. To investigate the functional relevance of mitochondria and aerobic glycolysis in T cells, we use T cell-specific knockout mice for Ptpmt1 (an enzyme essential for mitochondrial integrity) and Ldha (the key enzyme for aerobic glycolysis), respectively.

Results

Our data indicate a mitochondrial activation in T cells during NTN as measured by an increase in mitochondrial mass and mitochondrial membrane potential. Despite a strong dysregulation in T cell subsets in flow cytometry, mice with a mitochondrial dysfunction in T cells (CD4 Cre Ptpmt1 flox) show no differences in clinical parameters during NTN compared to wildtype mice. Analysis of metabolic dependencies with SCENITH points towards a strong dependence of kidney T cells on glycolysis in the diseased state, which was not observed in spleens or kidney draining lymph nodes. This finding is further investigated in mice with a T cell-specific Ldha knockout.

Conclusion

Kidney T cells rewire their metabolism in the NTN model by increasing both mitochondrial and glycolytic activity. Given the strong dependence on glycolysis seen in our SCENITH analyses and the lack of a difference in the clinical outcome in mice with a mitochondrial dysfunction in T cells, we hypothesize that the glycolytic activation is functionally more relevant for the pathological activity of T cells, which would be of great interest for therapeutic intervention.

Funding

• Government Support – Non-U.S.