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Kidney Week

Abstract: TH-OR35

A Glomerular Transcriptomic Landscape of APOL1 in Black Patients with Focal Segmental Glomerulosclerosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
  • Fermin, Damian, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Eichinger, Felix H., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Pollak, Martin R., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Friedman, David J., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Group or Team Name

  • Nephrotic Syndrome Study Network (NEPTUNE)
Background

Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black people. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1’s pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease.

Methods

With the hypothesis that the pathology driven by the high-risk (HR) APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black FSGS patients with a HR vs 14 with a low-risk (“LR”) APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways illuminated in these studies.

Results

We discovered (1) increased expression of APOL1 in HR and nine other significant differentially expressed genes, including stanniocalcin (STC1), which has a role in mitochondrial and calcium-related processes, (2) differential correlations between HR and LR APOL1 and metabolism pathway genes, but similar correlations with extracellular matrix- and immune-related genes, (3) significant loss of co-expression of mitochondrial genes in HR FSGS, and (4) an NF-kB -down-regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family and immune-related genes.

Conclusion

Overall, differences in mitochondrial gene regulation appear to underlie many differences observed between HR and LR FSGS. All data are available for secondary analysis through the “APOL1 Portal” (http://APOL1portal.org).