Gene expression profile in an interferon-exposed APOL1 high-risk transgenic mouse resembles expression profiles in urinary podocytes from subjects with APOL1 high-risk genotype

Authors

• N Anandanadarajah
• D Yeung
• Y Li
• A Talukder
• DM Umbach
• Z Fan
• L Li

Abstract

Coding genetic variants in apolipoprotein-L1 (APOL1) include APOL1-G0 (low-risk) and APOL1-G1, APOL1-G2 (high-risk) genotypes. A 13% of African-Americans (estimated six million individuals) carry two APOL1 risk variants and are at substantially increased risk for chronic kidney disease, including focal segmental glomerulosclerosis (FSGS) and arterionephrosclerosis. Although cellular effects of the APOL1 variants have been studied extensively in vitro, their effects on podocytes have not been characterized ex vivo at the single-cell resolution. Bacterial artificial chromosome (BAC)/APOL1 transgenic mice were administered retro-orbitally a single dose of interferon gamma to increase APOL1 expression. Mice were euthanized 24 hours later. Single-nucleus RNA sequencing was performed using isolated glomeruli from wild-type and BAC/APOL1-G0 and -G1 mice. Data from three mouse kidney glomerular samples (one from each genotype) showed three podocyte clusters reflecting healthy, mild injury and severe injury states. The cluster showing severe injury had the highest APOL1 expression. This cluster had high expression of genes related to epithelial-mesenchymal transition. Further, APOL1-G1-specific genes from the severe injury cluster were also more highly expressed in human FSGS APOL1 high-risk urinary podocytes, compared to low-risk urinary podocytes. In conclusion, following interferon gamma administration to BAC/APOL1 mice and prior to the appearance of glomerulosclerosis, we observed a unique gene expression profile in APOL1-G1 risk allele mice compared to APOL1-G0 mice. A similar gene expression profile was observed in APOL1 high-risk human urinary podocytes. This study identified an early signature of APOL1-G1 risk allele-mediated podocyte injury.

Scientific Focus Area: Cell Biology

This page was last updated on Monday, September 25, 2023