Potentiated JAK-STAT Signaling Differentiates Stem Cell-Derived Podocytes of Patients with APOL1-Associated FSGS from Those of Healthy Carriers with a High-Risk APOL1 Genotype

Background: An estimated 20% of the 6 millionBlack Americans who carry APOL1 high-risk genotype (HRG) will develop APOL1-kidney disease (AKD) in their lifetime, while the remaining 80% will remain free of AKD. There is an urgent, unmet need for predictive biomarkers that could distinguish the 20% at risk of AKD prior to the onset of the disease. Podocytopathy, including FSGS, is a key manifestation of AKD. We hypothesized that genetically-encoded differences in podocyte in response to AKD triggers, such as interferons, could explain the incomplete penetrance of AKD among carriers of HRG. Methods: To identify potential differences in interferon-gamma (IFN-γ)-induced podocyte gene expression that might lead to risk or protection from AKD, we generated iPSC-podocytes from 21 adults with HRG and biopsy-proven FSGS (high-risk (HR) cases) and 12 adults with HRG and normal eGFR and no proteinuria (HR controls). The iPSC-podocytes were treated with or without IFN-γ followed by whole genome transcriptomic analysis and compared with published transcriptome of laser-captured glomeruli of FSGS cases from the NEPTUNE cohort. Results: We discovered that IFN-γ induced higher expression of several genes including CXCL9, CXCL10CXCL11, and APOL1 in iPSC-podocytes of HR cases versus HR controls. The expression of these genes is regulated by JAK-STAT signaling. At baseline, there were no differences in JAK-STAT signaling between HR cases and HR controls. Our comparative analysis of iPSC-podocyte transcriptome with published glomeruli transcriptome from the NEPTUNE cohort confirmed that elevated JAK-STAT signaling is a common feature of HR cases in iPSC-podocytes and glomeruli. Conclusion: Our results identified potentiated JAK-STAT-mediated gene expression including chemokines in human iPSC-podocytes, which could serve as a predictive biomarker of APOL1-kidney disease. This promising finding suggests that measurement of IFN-γ-induced chemokine expression in iPSC-podocytes of HRG carriers could serve as a tool for predicting the likelihood of future incidence of AKD. Validation in a larger sample size would facilitate clinical translation of this finding. Funding: NIDDK Support - NIDDK Support, NIDDK Support