Abstract: SA-OR88
IFNγ-Induced APOL1 Expression and Pyroptotic Angiopathy in Human Kidney Organoids Mirrors a Nephrotic Gene Signature in Patient Biopsies
Session Information
- Glomerular Diseases: From Multiomics to Mechanisms
November 04, 2023 | Location: Room 103, Pennsylvania Convention Center
Abstract Time: 04:30 PM - 04:39 PM
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.
Edit
Fig2. Hypothetical model of IFNγ-mediated endothelial insult as a “second-hit” in APOL1-mediated nephropathy.
Funding
- Other NIH Support