Kidney Week

Abstract: TH-PO546

Analysis of Glomerular Transcriptomes from Nephrotic Patients Suggests APOL1 Risk Variants Impact Parietal Epithelial Cells

Session Information

• Glomerular Diseases: Omics, Biomarkers, and Tools
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Gonzalez-Vicente, Agustin, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States

Agustin Gonzalez-Vicente, PhD

• Crawford, Dana C., Case Western Reserve University School of Medicine, Cleveland, Ohio, United States

Dana C. Crawford, PhD

• Bush, William S., Case Western Reserve University School of Medicine, Cleveland, Ohio, United States

William S. Bush, MS, PhD

• Wu, Zhenzhen, Cleveland Clinic, Cleveland, Ohio, United States

Zhenzhen Wu

• Bruggeman, Leslie A., Cleveland Clinic, Cleveland, Ohio, United States

Leslie A. Bruggeman, PhD

• Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States

Viji Nair, PhD

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• O'Toole, John F., Cleveland Clinic, Cleveland, Ohio, United States

John F. O'Toole, MD

• Sedor, John R., Cleveland Clinic, Cleveland, Ohio, United States

John R. Sedor, MD, FASN

Group or Team Name

• Nephrotic Syndrome Study Network (NEPTUNE) and Kidney Precision Medicine Project (KPMP).

Background

Two APOL1 gene variants (G1 and G2), only present in individuals with African ancestry, are linked to increased kidney disease rates. The mechanisms behind this genetic association remain obscure. We hypothesized that individuals with APOL1 risk alleles have a glomerular transcriptional signature, which could identify candidate disease mechanisms.

Methods

We analyzed glomerular RNASeq transcriptomes from patients with idiopathic nephrotic syndrome, of which 72 had inferred African ancestry (AA) and 152 did not.

Results

Characteristic Direction identified a signature (SIG, 1481 genes), which separated AA patients with APOL1 risk alleles from those homozygous for reference APOL1. Kaplan-Meier (KM) analysis showed that AA patients in the highest tertile of SIG activation scores progressed faster to the composite event of kidney failure or loss of 40% eGFR (p≤0.013). In addition, we found an association between a gene coexpression metamodule (MM, 437 genes) and the number of APOL1 risk alleles, which remained significant after adjusting for eGFR and proteinuria. KM analysis showed that AA patients in the highest tertile of MM activation scores were less likely to achieve complete proteinuria remission (p≤0.014). SIG and MM activation scores did not associate with clinical outcomes in patients without inferred African ancestry. MM and SIG presented 191 common genes, and were both enriched for Epithelial Mesenchymal Transition (EMT) and inflammation terms. Overlap with glomerular cell identity signatures showed that MM predominantly features genes from parietal epithelial cells (PECs) rather than podocytes (PODs).

Conclusion

Concordant with enrichment in EMT genes, PECs could lose their epithelial phenotype while concomitantly driving glomerular scarring. These data suggest APOL1 nephropathy is mediated by cellular crosstalk, in which PODs expressing G1 or G2 variants have paracrine effects on PECs, perhaps mediated by inflammatory cytokines. Thus, the presence of APOL1 risk alleles may lead to persistent glomerular inflammation, PEC activation, podocyte loss, and glomerular scarring, thereby accelerating the progression of kidney disease.

Funding

• NIDDK Support