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Kidney Week

Abstract: FR-PO686

A Kidney Organoid-Derived Hypoxic Transcriptional Signature Correlates with Tubular Injury and Disease Progression in Focal Segmental Glomerulosclerosis (FSGS)/Minimal Change Disease (MCD)

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Minakawa, Akihiro, University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Berthier, Celine C., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Fischer, Matthew, University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • El Saghir, Jamal, University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Vega-Warner, V., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Menon, Rajasree, University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Hartman, John R., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Eichinger, Felix H., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Schaub, Jennifer A., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
  • Harder, Jennifer L., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
Background

Alterations in kidney tissue hypoxia are thought to contribute to kidney disease but the pathomechanism is unclear. The aim of our study was to investigate the relevance of a hypoxia molecular signature derived from a kidney organoid model to human kidney disease.

Methods

Kidney organoids (K-Orgs) were treated with 1% O2 for 24 h, and assessed by qPCR, bulk and single cell (sc) RNA-seq, IF and ELISA. A hypoxia signature was extracted from the differentially expressed genes in hypoxic vs. control K-Orgs. This signature was evaluated in bulk RNA-seq the kidney tissue expression profiles in the molecularly characterized FSGS/MCD NEPTUNE cohort (PMID: 36442540) and accompanied with morphometric scores of tubular injuries and the 3 previously computationally derived disease subclusters (C1~C3) and Living donors (LD).

Results

In hypoxic K-Orgs, IF confirmed HIF-1α nuclear accumulation, along with GLUT1 (IF) and secreted VEGFA (ELISA), and genes related to glycolysis and lactate synthesis (qPCR). sc RNA-seq confirmed HIF-1's target gene expression in kidney cell types (e.g. podocytes), and bulk RNA-seq revealed a total of 380 genes identified a hypoxia signature in hypoxic organoids. As shown in the figure, this signature was significantly higher in C3 that was identified with the poorest outcome. Tubular injury scores also correlated with hypoxic gene signature scores.

Conclusion

A transcriptional signature of hypoxic cell stress generated from a hypoxic K-Orgs was higher in the tubulointerstitial compartment of FSGS/MCD patients with poor outcome and correlated with morphometric evidence of tubular injury. These results suggest that kidney cell hypoxia is contributing to FSGS/MCD disease activity and progression.

Figure. NEPTUNE cohort

Funding

  • NIDDK Support – Eli Lilly