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Abstract: SA-OR37

Upregulated JAK-STAT Signaling and Augmented Potassium Efflux Characterize Induced Pluripotent Stem Cell-Derived Podocytes of Black Patients with APOL1-Associated FSGS

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

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

High risk (HR) APOL1 genotypes account for 70% of excess risk of FSGS among Blacks. It is unknown why ~20% of carriers of HR APOL1 genotypes develop FSGS or other APOL1 nephropathies while 80% kidney disease-free. The possible role of genetic modifiers has been proposed. Also, the mechanism by which variants APOL1 cause podocyte injury is unknown. We previously reported that overexpression of variants APOL1 in HEK293 cells caused cytotoxic loss of cellular K+. it is unknown if physiologic expression of APOL1 by IFNγ also causes K+ loss in patient-derived podocytes.

Methods

We recruited Blacks with biopsy-proven FSGS (n=16) or with normal GFR and no proteinuria (n=20). 68.7% and 10% of FSGS cases and healthy controls carried HR APOL1 genotypes, respectively. Markers-confirmed iPSC-podocytes generated from 7 HR cases and 2 HR controls were treated or not with IFNγ followed by whole genome transcriptomics and measurement of cellular K+. Additionally, APOL1-knockout iPSC-podocytes were generated using CRISPR-Cas9.

Results

Notably, the 520 differentially expressed genes (DEGs) unique to HR cases are transcriptionally regulated by JAK-STAT signaling (Fig. A-B). Consistent with this finding, IFNγ induces a higher expression of APOL1 in HR cases which was blocked by JAK1/2-specific inhibitor, Baricitinib ( Fig C). Importantly, for the first time, we demonstrated that physiologic expression of variant APOL1 under its endogenous promoter causes significant loss of cellular K+ in iPSC-podocyte of HR cases and was abolished by APOL1-knockout (Fig D-E).

Conclusion

JAK-STAT signaling may be an important modifier of APOL1-associated FSGS that upregulates APOL1 expression and function (K+ efflux). Inhibition of JAK-STAT signaling and/or blockade of APOL1-mediated cation-transport may represent targeted therapeutic approach for APOL1-associated FSGS.

IFNγ induces higher JAK-STAT signaling, APOL1 expression and Rb+ efflux in iPSC-podocytes of HR cases. APOL1 KO blocks Rb+ efflux.

Funding

  • Other NIH Support