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Freedman’s Lab Uncovers IFN-γ's Role in Kidney Disease Progression
Jun 6, 2024
We are proud to present a new publication from the ReBuilding a Kidney (RBK) consortium, led by Benjamin S. Freedman (University of Washington), that offers crucial insights into the role of interferon-γ (IFN-γ) in kidney disease.
Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease
Authors: 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 and Benjamin S. Freedman Journal: Cell Reports DOI: https://doi.org/10.1016/j.celrep.2024.114310
Summary:
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.
