Kidney Week

Abstract: SA-PO624

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

Session Information

• Genetic Kidney Diseases: Models, Mechanisms, and Therapies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Datta, Somenath, Duke University, Durham, North Carolina, United States

Somenath Datta, MSc, PhD

• Soldano, Karen, Duke University, Durham, North Carolina, United States

Karen Soldano

• Silas, Daniel Philip, Duke University, Durham, North Carolina, United States

Daniel Philip Silas

• Li, Guojie, Duke University, Durham, North Carolina, United States

Guojie Li, PhD

• Nystrom, Sarah, Duke University, Durham, North Carolina, United States

Sarah Nystrom, MD, MPH

• Garrett, Melanie E., Duke University, Durham, North Carolina, United States

Melanie E. Garrett, MS

• Ashley-Koch, Allison, Duke University, Durham, North Carolina, United States

Allison Ashley-Koch, PhD

• Olabisi, Opeyemi A., Duke University, Durham, North Carolina, United States

Opeyemi A. Olabisi, MD, PhD

Background

An estimated 20% of the 6 million Black 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, CXCL10 CXCL11, 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