Single-Cell Transcriptional Signatures of Glomerular Disease in Transgenic Mice with APOL1 Variants.

Abstract

APOL1 high-risk variants contribute to kidney disease among African-ancestry individuals. We sought to describe cell-specific APOL1 variants-induced pathways using two mouse models. We characterized bacterial artificial chromosome (BAC)/APOL1 transgenic mice crossed with HIV-associated nephropathy (HIVAN) Tg26 mice and BAC/APOL1 transgenic mice given interferon-γ. Both mouse models showed more severe glomerular disease in APOL1-G1 compared to APOL1-G0 mice. Bulk RNA-seq of HIVAN model-glomeruli identified synergistic podocyte-damaging pathways activated by APOL1-G1 and by the HIV transgene. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially-expressed genes as a function of APOL1 alleles. Shared activated pathways, e.g. mTOR, and differentially-expressed genes, e.g. Ccn2, in podocytes in both models suggest novel markers of APOL1-associated kidney disease. HIVAN mouse-model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis glomerular RNA-seq data. Differential effects of the APOL1-G1 variant on the eukaryotic Initiation factor-2 pathway highlighted differences between the two models. These findings in two mouse models demonstrated both shared and distinct cell type-specific transcriptomic signatures induced by APOL1 variants. These findings suggest novel therapeutic opportunities for APOL1 glomerulopathies.