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

Publication ,  Journal Article
Nystrom, SE; Li, G; Datta, S; Soldano, KL; Silas, D; Weins, A; Hall, G; Thomas, DB; Olabisi, OA
Published in: JCI Insight
June 8, 2022

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

June 8, 2022

Volume

7

Issue

11

Location

United States

Related Subject Headings

  • Sulfonamides
  • Signal Transduction
  • STAT Transcription Factors
  • SARS-CoV-2
  • Pyrazoles
  • Purines
  • Organoids
  • Kidney Diseases
  • Janus Kinases
  • Janus Kinase Inhibitors
 

Citation

APA
Chicago
ICMJE
MLA
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Nystrom, S. E., Li, G., Datta, S., Soldano, K. L., Silas, D., Weins, A., … Olabisi, O. A. (2022). JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight, 7(11). https://doi.org/10.1172/jci.insight.157432
Nystrom, Sarah E., Guojie Li, Somenath Datta, Karen L. Soldano, Daniel Silas, Astrid Weins, Gentzon Hall, David B. Thomas, and Opeyemi A. Olabisi. “JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.JCI Insight 7, no. 11 (June 8, 2022). https://doi.org/10.1172/jci.insight.157432.
Nystrom SE, Li G, Datta S, Soldano KL, Silas D, Weins A, et al. JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11).
Nystrom, Sarah E., et al. “JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.JCI Insight, vol. 7, no. 11, June 2022. Pubmed, doi:10.1172/jci.insight.157432.
Nystrom SE, Li G, Datta S, Soldano KL, Silas D, Weins A, Hall G, Thomas DB, Olabisi OA. JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

June 8, 2022

Volume

7

Issue

11

Location

United States

Related Subject Headings

  • Sulfonamides
  • Signal Transduction
  • STAT Transcription Factors
  • SARS-CoV-2
  • Pyrazoles
  • Purines
  • Organoids
  • Kidney Diseases
  • Janus Kinases
  • Janus Kinase Inhibitors