JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.

dc.contributor.author

Nystrom, Sarah E

dc.contributor.author

Li, Guojie

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Datta, Somenath

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Soldano, Karen L

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Silas, Daniel

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Weins, Astrid

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Hall, Gentzon

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Thomas, David B

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Olabisi, Opeyemi A

dc.date.accessioned

2024-06-01T15:35:05Z

dc.date.available

2024-06-01T15:35:05Z

dc.date.issued

2022-06

dc.description.abstract

COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.

dc.identifier

157432

dc.identifier.issn

2379-3708

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2379-3708

dc.identifier.uri

https://hdl.handle.net/10161/30755

dc.language

eng

dc.publisher

American Society for Clinical Investigation

dc.relation.ispartof

JCI insight

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10.1172/jci.insight.157432

dc.rights.uri

https://creativecommons.org/licenses/by-nc/4.0

dc.subject

Organoids

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Endothelial Cells

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Humans

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Kidney Diseases

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Sulfonamides

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Azetidines

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Pyrazoles

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Purines

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Cytokines

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Signal Transduction

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STAT Transcription Factors

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Janus Kinases

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Janus Kinase Inhibitors

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Apolipoprotein L1

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COVID-19

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SARS-CoV-2

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COVID-19 Drug Treatment

dc.title

JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.

dc.type

Journal article

duke.contributor.orcid

Nystrom, Sarah E|0000-0002-1094-1483

duke.contributor.orcid

Olabisi, Opeyemi A|0000-0003-0886-7605

pubs.begin-page

e157432

pubs.issue

11

pubs.organisational-group

Duke

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School of Medicine

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Clinical Science Departments

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Institutes and Centers

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Medicine

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Medicine, Nephrology

pubs.organisational-group

Duke Molecular Physiology Institute

pubs.publication-status

Published

pubs.volume

7

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