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

doi:10.1016/j.celrep.2024.114310

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^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English (US)
Article number	114310
Journal	Cell reports
Volume	43
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2024.114310
State	Published - Jun 25 2024

Funding

We thank Byungha Chung and Rebecca Hjorten for preliminary studies on APOL1 immunolocalization and Abhijit S. Naik for helpful discussions. Illustrations were created with BioRender.com. Studies were supported by NIH awards R01DK130386 (B.S.F. K.D.S. and S.A.), R01DK117914 (B.S.F.), UH3TR000504 (J.H.), UH3TR002158 (J.H.), UH3TR03288 (J.H. and M.K.), U01DK127553 (B.S.F.), U01AI176460 (B.S.F.), R01HL167688 (H.F.), R35GM149516 (H.F.), and 5UC2DK126006 (Stuart Shankland and B.S.F.); Department of Defense awards W81XWH-21-1-0006 and W81XWH-21-1-0007 (B.S.F. and Hannele Ruohola-Baker); DOD Kidney Cancer Research Program Translational Research Partnership Award KC180135 (S.A. and Scott S. Tykodi); and NASA contract #80ARC023CA001. B.S.F. and B.A.J. conceived the project with input from K.D.S. Y.Z. J.L.H. M.K. and J.H. B.A.J. H.F. J.L.H. J.L. Y.Z. and B.S.F. designed the experiments. B.A.J. I.B.S. F.S. H.F. J.E.S. J.L.H. S.E. K.D.S. S.A. E.L. P.K.B. J.Y. Y.Z. and B.S.F. performed the experiments and analyzed the data. B.A.J. and B.S.F. wrote the paper with input from all authors. B.S.F. is an inventor on patents and/or patent applications related to human kidney organoid differentiation and modeling of disease in this system (these include \u201CThree-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human microphysiology, toxicology, and morphogenesis\u201D [Japan, US, and Australia], licensed to STEMCELL Technologies; \u201CHigh-throughput automation of organoids for identifying therapeutic strategies\u201D [PTC patent application pending]; and \u201CSystems and methods for characterizing pathophysiology\u201D [PTC patent application pending]). B.S.F. and H.F. hold ownership interest in Plurexa, LLC. None of the preceding interests affected in any way the results of the paper or would be affected by them but are shared by way of transparency. We thank Byungha Chung and Rebecca Hjorten for preliminary studies on APOL1 immunolocalization. We thank Stuart Shankland, Hannele Ruohola-Baker, Scott S. Tykodi, and Abhijit S. Naik. Illustrations were created with BioRender.com . Studies were supported by NIH awards R01DK130386 (B.S.F., K.D.S., and R.A.), R01DK117914 (B.S.F.), UH3TR000504 (J.H.), UH3TR002158 (J.H.), UH3TR03288 (J.H. and M.K.), U01DK127553 (B.S.F.), and 5UC2DK126006 (S.J.S.); Department of Defense awards W81XWH-21-1-0006 and W81XWH-21-1-0007 (B.S.F. and H.R.B.); DOD Kidney Cancer Research Program Translational Research Partnership Award KC180135 (S.A. and S.S.T.); and NASA Proposal #21-3DTMPS_2-0001.

Keywords

CP: Cell biology
CP: Immunology
baricitinib
caspase
cell death
gasdermin
glomerulosclerosis
inflammation
podocalyxin
proteomics
pyroptosis
spatial transcriptomics

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2024.114310

Cite this

Juliar, B. A., Stanaway, I. B., Sano, F., Fu, H., Smith, K. D., Akilesh, S., Scales, S. J., El Saghir, J., Bhatraju, P. K., Liu, E., Yang, J., Lin, J., Eddy, S., Kretzler, M., Zheng, Y., Himmelfarb, J., Harder, J. L., & Freedman, B. S. (2024). Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease. Cell reports, 43(6), Article 114310. https://doi.org/10.1016/j.celrep.2024.114310

@article{e8a6fd3f617241bd89951bdab31d83ee,

title = "Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease",

abstract = "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.",

keywords = "CP: Cell biology, CP: Immunology, baricitinib, caspase, cell death, gasdermin, glomerulosclerosis, inflammation, podocalyxin, proteomics, pyroptosis, spatial transcriptomics",

author = "Juliar, {Benjamin A.} and Stanaway, {Ian B.} and Fumika Sano and Hongxia Fu and Smith, {Kelly D.} and Shreeram Akilesh and Scales, {Suzie J.} and {El Saghir}, Jamal and Bhatraju, {Pavan K.} and Esther Liu and Johnson Yang and Jennie Lin and Sean Eddy and Matthias Kretzler and Ying Zheng and Jonathan Himmelfarb and Harder, {Jennifer L.} and Freedman, {Benjamin S.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = jun,

day = "25",

doi = "10.1016/j.celrep.2024.114310",

language = "English (US)",

volume = "43",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

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Juliar, BA, Stanaway, IB, Sano, F, Fu, H, Smith, KD, Akilesh, S, Scales, SJ, El Saghir, J, Bhatraju, PK, Liu, E, Yang, J, Lin, J, Eddy, S, Kretzler, M, Zheng, Y, Himmelfarb, J, Harder, JL & Freedman, BS 2024, 'Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease', Cell reports, vol. 43, no. 6, 114310. https://doi.org/10.1016/j.celrep.2024.114310

TY - JOUR

T1 - Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease

AU - Juliar, Benjamin A.

AU - Stanaway, Ian B.

AU - Sano, Fumika

AU - Fu, Hongxia

AU - Smith, Kelly D.

AU - Akilesh, Shreeram

AU - Scales, Suzie J.

AU - El Saghir, Jamal

AU - Bhatraju, Pavan K.

AU - Liu, Esther

AU - Yang, Johnson

AU - Lin, Jennie

AU - Eddy, Sean

AU - Kretzler, Matthias

AU - Zheng, Ying

AU - Himmelfarb, Jonathan

AU - Harder, Jennifer L.

AU - Freedman, Benjamin S.

PY - 2024/6/25

Y1 - 2024/6/25

N2 - 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.

AB - 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.

KW - CP: Cell biology

KW - CP: Immunology

KW - baricitinib

KW - caspase

KW - cell death

KW - gasdermin

KW - glomerulosclerosis

KW - inflammation

KW - podocalyxin

KW - proteomics

KW - pyroptosis

KW - spatial transcriptomics

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UR - http://www.scopus.com/inward/citedby.url?scp=85194834818&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2024.114310

DO - 10.1016/j.celrep.2024.114310

M3 - Article

C2 - 38838223

AN - SCOPUS:85194834818

SN - 2211-1247

VL - 43

JO - Cell reports

JF - Cell reports

IS - 6

M1 - 114310

ER -

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

Abstract

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UN SDGs

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