Abstract: TH-PO421
Metabolic Responses in Human Kidney Organoids to Tumor Necrosis Factor-Alpha Stimulation: Integration of Proteomic and Metabolomic Signatures
Session Information
- Development, Organoids, Injury, and Regeneration
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 600 Development, Stem Cells, and Regenerative Medicine
Authors
- Lassé, Moritz, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Harder, Jennifer L., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Laufer, Sandra D., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Braun, Fabian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Rinschen, Markus M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Group or Team Name
- Rinschen Lab.
Background
Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in systemic inflammation and has a profound impact on metabolic processes within cells. Studying its effects on kidney cells using organoids can reveal insights into renal inflammatory responses and metabolic dysregulation associated with kidney diseases. This study aimed to identify and analyze the metabolic shifts in human kidney organoids following TNF-alpha treatment, focusing on energy metabolism, amino acid metabolism and generation of uremic toxins.
Methods
TNF-alpha exposed Kidney organoids were analyzed using proteomics and targeted metabolomic mass spectrometric analyses. Altered metabolites were integrated with proteome-scale networks. We quantified changes in key catalytic enzymes and metabolites involved in major metabolic pathways including the citric acid cycle, amino acid metabolism, and the production of known uremic toxins.
Results
TNF-alpha stimulation resulted in significant metabolic rewiring of the organoid cells. We observed altered protein expression upon TNF-alpha exposure, particularly in amino acid, energy, and nucleotide metabolism. Top proteins involved were associated with adverse clinical outcomes in proteinuric disease in the NEPTUNE cohort. Enhanced energy demand was evident by an increased production of TCA cycle metabolites. Crucially, we also detected increased metabolite markers of kidney injury, inflammation, amino acid metabolism and apoptosis to be upregulated. Conversely, there was a marked decrease of metabolites related to energy production, nucleotide synthesis, and protein synthesis. These downregulated metabolites highlight a possible reduction in biosynthetic and energy-related processes under inflammatory conditions. Altered metabolites were integrated with proteome-scale networks.
Conclusion
TNF-alpha induces complex metabolic responses in human kidney organoids, characterized by orchestrated response of shifts in critical
metabolites across various pathways. The observed metabolic reprogramming may represent an adaptive response to inflammation or a pathogenic mechanism contributing to disease progression. These findings emphasize the importance of renal metabolic responses to inflammation and may guide future therapeutic strategies targeting metabolic disturbances in kidney diseases.