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 organoids can reveal insights into renal inflammatory responses and metabolic dysregulation associated with kidney diseases. This study aimed to characterize metabolic shifts in human kidney organoids upon TNF-alpha stimulation, with a focus on energy metabolism, amino acid metabolism, and uremic toxin production, and to test whether supplementation with TCA cycle metabolites could modulate these effects. Methods: Kidney organoids were exposed to TNF-alpha, followed by proteomics and metabolomics mass spectrometric analyses. We quantified changes in key catalytic enzymes and metabolites involved in major metabolic pathways including the TCA cycle, amino acid metabolism, and the production of uremic toxins. In a follow-up experiment we combined TNF-alpha treatment with a TCA cycle metabolite mix (500µM each of cis-aconitic acid, citric acid, sodium succinate, and L-malic acid) to assess whether TCA cycle metabolites can attenuate the TNF-alpha–induced inflammation. Results: TNF-alpha stimulation resulted in significant metabolic rewiring of the organoid tissue. We observed an increased energy demand evidenced by upregulated production of TCA cycle metabolites. Further, we detected changes in fatty acid, amino acid and nucleotide metabolism. Importantly, co-treatment of organoids with TNF-alpha and the TCA cycle metabolite mix partially ameliorated the inflammatory response: concentrations of C3, VCAM1, and CXCL10 were reduced at both 24h and 48h compared to TNF-alpha alone, suggesting a protective effect of the metabolites. Conclusion: TNF-alpha induces a coordinated inflammatory response and metabolic reprogramming in human kidney organoids. Supplementation with TCA cycle intermediates can mitigate key inflammatory markers, pointing to a potential therapeutic strategy for metabolic modulation in kidney inflammation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Lassé et al. (Fri,) studied this question.