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Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease.

Benjamin A Juliar | Ian B Stanaway | Fumika Sano | Hongxia Fu | Kelly D Smith | Shreeram Akilesh | Suzie J Scales | Jamal El Saghir | Pavan K Bhatraju | Esther Liu | Johnson Yang | Jennie Lin | Sean Eddy | Matthias Kretzler | Ying Zheng | Jonathan Himmelfarb | Jennifer L Harder | Benjamin S Freedman
Cell reports | 2024

Elevated interferon (IFN) signaling is associated with kidney diseases including COVID-19, HIV, and apolipoprotein-L1 (APOL1) nephropathy, but whether IFNs directly contribute to nephrotoxicity remains unclear. Using human kidney organoids, primary endothelial cells, and patient samples, we demonstrate that IFN-γ induces pyroptotic angiopathy in combination with APOL1 expression. Single-cell RNA sequencing, immunoblotting, and quantitative fluorescence-based assays reveal that IFN-γ-mediated expression of APOL1 is accompanied by pyroptotic endothelial network degradation in organoids. Pharmacological blockade of IFN-γ signaling inhibits APOL1 expression, prevents upregulation of pyroptosis-associated genes, and rescues vascular networks. Multiomic analyses in patients with COVID-19, proteinuric kidney disease, and collapsing glomerulopathy similarly demonstrate increased IFN signaling and pyroptosis-associated gene expression correlating with accelerated renal disease progression. Our results reveal that IFN-γ signaling simultaneously induces endothelial injury and primes renal cells for pyroptosis, suggesting a combinatorial mechanism for APOL1-mediated collapsing glomerulopathy, which can be targeted therapeutically.

Pubmed ID: 38838223 RIS Download

Associated grants

  • Agency: NCATS NIH HHS, United States
    Id: UH3 TR000504
  • Agency: NIDDK NIH HHS, United States
    Id: UC2 DK126006
  • Agency: NCATS NIH HHS, United States
    Id: UH3 TR002158
  • Agency: NCATS NIH HHS, United States
    Id: UH3 TR003288
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM149516
  • Agency: NCATS NIH HHS, United States
    Id: U2C TR004867
  • Agency: NIAID NIH HHS, United States
    Id: U01 AI176460
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL167688
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK117914
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK130386
  • Agency: NIDDK NIH HHS, United States
    Id: TL1 DK132769
  • Agency: NIDDK NIH HHS, United States
    Id: U01 DK127553

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