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Abstract: PO0003

Deciphering the Impact of Cytokine Storm on APOL1 Expression in Primary Human Glomerular Endothelial Cells

Session Information

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Nystrom, Sarah, Duke University School of Medicine, Durham, North Carolina, United States
  • Datta, Somenath, Duke University School of Medicine, Durham, North Carolina, United States
  • Soldano, Karen, Duke University School of Medicine, Durham, North Carolina, United States
  • Olabisi, Opeyemi A., Duke University School of Medicine, Durham, North Carolina, United States
Background

High Risk (HR) Apolipoprotein L1 (APOL1) genotypes are associated with collapsing glomerulopathy in the context of interferons (IFNs), HIV, systemic lupus erythematous (SLE), and SARS-CoV2 infection. Elevated circulating inflammatory cytokines, commonly referred to as “cytokine storm” are believed to play causal role in disease pathogenesis. Although the role of IFN and TNF in APOL1 induction has been described, it is unknown if other components of “cytokine storm” implicated in COVAN and lupus glomerulopathy also induce APOL1 expression. In vitro and animal studies show that expression of variant APOL1 is sufficient to cause glomerulopathy in dose-dependent manner. Therefore, it is important to establish if other components of “cytokine storm” regulate APOL1 expression in human glomerular compartment.

Methods

We evaluate the direct effect of cytokines implicated in the above diseases on APOL1 expression in primary human glomerular endothelial cells, a cell type with known significance in lupus and COVAN. We also screened these select cytokines using peripheral blood monocytes (PBMCs) from patient with SLE and HR APOL1 genotype.

Results

IFNs(β>γ>α) were the strongest drivers of APOL1 expression. Importantly, we also found that IL-6 increased APOL1 expression by 7 fold compared to control (p<0.01) in glomerular endothelial cells. Treatment with composite of all cytokines induced the most robust APOL1 expression. However, Jak 1/2-specific inhibitor, baricitinib, markedly attenuated this effect, with reduction in APOL1 expression from 800 fold down to 4 fold. Additionally, in PBMCs of a lupus patient with HR APOL1, IL-18 also showed significant upregulation of APOL1 expression.

Conclusion

Our data suggest that other cytokines beyond interferon may be important in the pathogenesis of COVAN, HIVAN, and APOL1-associated lupus collapsing glomerulopathy and that Jak-inhibitors may be a promising novel therapeutic in these cytokine-mediated APOL1 nephropathies.

Cytokine Regulation of APOL1

Funding

  • Other NIH Support