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Abstract: TH-PO640

Stem Cell-Derived Podocytes from Blacks with FSGS and High Risk ApoL1 Expressed More ApoL1 Protein and Reduced Viability in Response to Interferon γ

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

  • Olabisi, Opeyemi A., Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Moore, Savannah, Massachusetts General Hospital, Brookline, Massachusetts, United States
  • Kataria, Rama, Harvard Medical SChool, Boston, Massachusetts, United States
Background

Podocyte injury/loss is the cellular hallmark of ApoL1-nephropathies. Blacks with high risk (HR) ApoL1 alleles (G1G1, G2G2, or G1G2) have 7-10-fold increased risk of Focal segmental glomerulosclerosis (FSGS). HR ApoL1 is sensitive but not specific for FSGS. Estimated 20% of carriers of HR ApoL1 develop ApoL1-nephropathy. There is need for functional assay to identify truly at-risk blacks. Lack of disease-relevant podocyte model has stalled research progress. Our goal is to utilize stem-cell derived podocytes as tools for determining an individual’s risk of ApoL1-nephropathy.

Methods

We recruited blacks with biopsy-proven FSGS (cases) and healthy controls with normal GFR and no proteinuria. ApoL1 was genotyped by sanger sequencing. Induced pluripotent stem cells (iPSCs) generated from PBMCs were differentiated into markers-confirmed podocytes based on published protocol. Podocytes were treated/not with interferon γ (IFNγ). Cell viability, comparative transcriptome, and protein expression were determined by cellular ATP content, RNA-seq and immunoblotting, respectively.

Results

81.8% (9 of 11) cases have HR ApoL1 allele versus 16.7% (1 of 6) of controls. IFNγ induced higher ApoL1 protein expression in podocytes derived from cases despite similar intergroup ApoL1 mRNA levels. IFNγ reduced the viability of podocytes derived from cases with HR ApoL1 but not of controls, including control with HR ApoL1 genotype. Transcriptome analysis shows that IFNγ differentially upregulated genes involved in endocytic recycling, PI3K-mediated signaling, and actin filament-based movement in podocytes derived from cases.

Conclusion

iPSC- podocytes of blacks with ApoL1-nephropathies have a distinct cellular/molecular response to IFNγ which could be harnessed for Identification of blacks most at risk to develop ApoL1-nephropathy in future.

IFNγ induces higher ApoL1 protein & reduces viability of iPSC-podocytes of blacks with HR ApoL1 & FSGS/collapsing GN, CGN. Not applicable, NA

Funding

  • Private Foundation Support