Abstract: FR-PO919
APOL1 Kidney Disease-Associated Variants Induce Differential Glomerular Expression of Immune Sensory Proteins in FSGS
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Madhavan, Sethu M., Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Shapiro, John P., Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Cassol, Clarissa Araujo, Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Parikh, Samir V., Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Rovin, Brad H., Ohio State University Wexner Medical Center, Columbus, Ohio, United States
Background
Variants in APOL1 (G1 and G2) associate with increased risk of CKD including hypertension-related CKD and focal segmental glomerulosclerosis (FSGS) in individuals with West African ancestry. Mechanisms by which the APOL1 variants contribute to the pathogenesis of CKD is not well understood. We hypothesized that variant APOL1 proteins mediate kidney disease through pathways independent from reference APOL1 protein. We aimed at characterizing differentially regulated protein networks in glomeruli of FSGS patients in presence of APOL1 variants.
Methods
Formalin-fixed paraffin-embedded kidney biopsies with a diagnosis of primary FSGS with (n=3) and without (n=3) homozygous APOL1 risk variants and normal donor kidney biopsies (n=5) were identified. Glomeruli were isolated from the biopsies using laser capture microdissection followed by protein recovery, trypsin digestion and HPLC MS/MS using an Orbitrap fusion mass spectrometer. Label-free quantification in combination with global normalization of spectral count data was performed to determine changes in protein expression. Comparison of protein expression levels and upstream regulatory pathways were performed using Ingenuity Pathway Analysis software.
Results
In patients with FSGS, HLA-DQB1, HLA-DQA1 and ICAM-1 were significantly upregulated in the glomeruli in the presence of homozygous APOL1 variants. Interferon-gamma regulated pathways were upregulated in glomeruli of FSGS patients in the presence of homozygous APOL1 variants compared to FSGS with no APOL1 variants and normal donor kidney.
Conclusion
Upregulation of immune sensory proteins in glomeruli in presence of APOL1 variants suggests that a differential cellular immune response mediated by the variants could contribute to the pathogenesis of FSGS. A larger cohort of patient samples needs to be interrogated to validate the observation.