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Kidney Week

Abstract: SA-OR88

IFNγ-Induced APOL1 Expression and Pyroptotic Angiopathy in Human Kidney Organoids Mirrors a Nephrotic Gene Signature in Patient Biopsies

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Juliar, Benjamin A., University of Washington School of Medicine, Seattle, Washington, United States
  • Stanaway, Ian Byrell, University of Washington School of Medicine, Seattle, Washington, United States
  • Smith, Kelly D., University of Washington School of Medicine, Seattle, Washington, United States
  • Harder, Jennifer L., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Eddy, Sean, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Himmelfarb, Jonathan, University of Washington School of Medicine, Seattle, Washington, United States
  • Freedman, Benjamin S., University of Washington School of Medicine, Seattle, Washington, United States
Background

The cytokine interferon-γ (IFNγ) is an essential mediator of the innate immune response, including induction of apolipoprotein L1 (APOL1). Risk variants of APOL1 can cause glomerular nephropathy in coordination with inflammatory stimuli, but how distinct nephron segments are affected by IFNγ itself during glomerular disease progression remains poorly characterized.

Methods

Cell-type dependent changes in organoid gene expression and morphometrics were quantified with single-cell RNA sequencing and quantitative fluorescence-based assays. RNA-sequencing of kidney biopsies quantified relative differences in gene expression between patient cohorts depending on disease severity.

Results

IFNγ-mediated expression of APOL1 in wild-type kidney organoids was accompanied by endothelial network degradation (Fig1A) and upregulation of pyroptosis-associated genes across organoid cell types, especially endothelial cells (ECs) (Fig1B). Transcriptional profiling identified a similar pyroptotic gene signature in biopsies from patients with poor clinical outcomes. Pharmacological blockade of IFNγ signaling inhibited APOL1 expression, prevented upregulation of pyroptosis-associated genes, and rescued the endothelial network in organoids.

Conclusion

Our results suggest that simultaneous triggering of endothelial insult and epithelial priming towards pyroptosis by IFNγ may synergistically contribute to APOL1-mediated disease progression (Fig2), which can be targeted therapeutically.

Fig1. (A) JAK½ inhibition prevents IFN-γ-induced APOL1 upregulation and degradation of endothelial networks. (B) scRNA-seq reveals a pronounced pyroptotic gene signature in organoid ECs.
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Fig2. Hypothetical model of IFNγ-mediated endothelial insult as a “second-hit” in APOL1-mediated nephropathy.

Funding

  • Other NIH Support