Kidney Week

Abstract: SA-PO0741

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

Session Information

• Glomerular Diseases: Profiling Through Multiomics
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Nies, Jasper Friedrich, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Jasper Friedrich Nies, MD

• Sierra Gonzalez, Claudio, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Claudio Sierra Gonzalez, MS, MSc

• Trinsch, Bastian, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Bastian Trinsch

• Diefenhardt, Paul, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Paul Diefenhardt, MD

• Eckey, Tobias, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Tobias Eckey, MS

• Puetz, David L., Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

David L. Puetz

• Schermer, Bernhard, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Bernhard Schermer, MD

• Benzing, Thomas, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Thomas Benzing, MD, PhD, FASN

• Brinkkoetter, Paul T., Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Paul T. Brinkkoetter, MD

• Braehler, Sebastian, Universitatsklinikum Koln Klinik II fur Innere Medizin Nephrologie Rheumatologie Diabetologie und Allgemeine Innere Medizin, Cologne, NRW, Germany

Sebastian Braehler, MD

Background

Crescentic glomerulonephritis (cGN) is a severe, T cell-mediated autoimmune disorder with limited treatment options. The availability and use of various metabolites play a critical role in T cell activation and function. However, how oxidative phosphorylation and glycolysis influence T cell fate and behavior during cGN remains poorly understood, despite its central importance to disease pathogenesis. Understanding the metabolic pathways governing inflammatory T cell function may pave the way for novel therapeutic strategies.

Methods

To study T cell metabolism in autoimmune kidney disease, we employ the nephrotoxic nephritis (NTN) model. Given the low abundance of T cells in murine kidneys, we utilize single-cell approaches, including immunometabolic assays via flow cytometry (SCENITH) and analysis of human and murine single-cell RNA sequencing (scRNAseq) data. To assess the functional role of aerobic glycolysis in T cells, we use T cell-specific knockout mice for Ldha (a key enzyme in aerobic glycolysis) and characterized their CD4+ T cells under NTN and in vitro.

Results

Our results demonstrate that T cell activation in both humans and wild-type mice with cGN is characterized by a preferential reliance on aerobic glycolysis. Mice with a T cell-specific deletion of Ldha (CD4-Cre Ldha^flox; Ldha T-KO) develop significantly fewer glomerular crescents compared to controls. This is accompanied by a marked reduction in CD44+CD62L- effector CD4+ T cells and diminished Th1 polarization. In vitro, CD4+ T cells from Ldha T-KO mice exhibit significantly impaired proliferative capacity and increased susceptibility to cell death following CD3/CD28 stimulation. Longitudinal metabolomic analyses post-activation reveal that, due to impaired glycolytic flux, Ldha T-KO cells divert accumulating metabolites into the pentose phosphate pathway.

Conclusion

Kidney T cells rewire their metabolism in the NTN model by favoring glycolytic activity. Inhibition of aerobic glycolysis by genetic depletion in T cells reduced morphological kidney damage and strongly reduced effector and Th1 functions in CD4+ T cells. These findings could pave the way for a new therapeutic approach in T-cell driven kidney autoimmunity.

Funding

• Government Support – Non-U.S.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20255kb27vw0