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Kidney Week

Abstract: TH-PO541

An Integrated Proteome-Transcriptome Organoid Atlas Illuminates Core Concepts of Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Lassé, Moritz, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • El Saghir, Jamal, Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
  • Berthier, Celine C., Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
  • Eddy, Sean, Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
  • Fischer, Matthew, Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
  • Harder, Jennifer L., Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
  • Rinschen, Markus M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

The use of kidney organoids as a model for studying kidney disease shows great promise, but their potential is limited by our limited understanding of the proteins they express and their functional profiles. In this study, we aimed to address this limitation by examining the proteome and transcriptome of organoids throughout their culture period and in response to TNFα, a cytokine stressor.

Methods

In our study, we employed proteomic analysis to compare kidney organoids with other established model systems and native tissues, including native glomeruli and cultured podocytes. We examined the developmental trajectory of organoids and explored their innate immune responses, thereby expanding the applicability of organoids as a valuable model system in the field of nephrology. Additionally, we performed a comprehensive comparison of our proteomic data with both bulk and single-cell transcriptomics data, providing a more comprehensive understanding of the molecular landscape of kidney organoids.

Results

We found that older organoids displayed increased accumulation of extracellular matrix while showing decreased expression of glomerular proteins. By integrating single-cell transcriptome data, we discovered that most changes in the proteome were localized to podocytes, tubular cells, and stromal cells. Treatment of the organoids with TNFα resulted in the differential expression of 322 proteins, including cytokines and complement components. Importantly, the transcript expression of these 322 proteins was significantly higher in individuals with poorer clinical outcomes in proteinuric kidney disease. Notably, key proteins associated with TNFα (C3 and VCAM1) were found to be increased in both human tubular and organoid kidney cell populations, indicating the potential of organoids to advance the development of biomarkers. VCAM1 was localized to the descending thin limb (DTL) of proteinuric patients with kidney disease.

Conclusion

By integrating various "omic" layers of kidney organoids, incorporating a relevant cytokine stressor, and comparing with human data, we highlight the significance of kidney organoid modeling in understanding and studying complex human kidney disease.

Funding

  • NIDDK Support