Analysis of Glomerular Transcriptomes from Nephrotic Patients Suggest APOL1 Risk Variants Impact Parietal Epithelial...

Area of Science:

• Genetics and Genomics
• Nephrology
• Molecular Biology

Background:

• Black individuals exhibit a disproportionately higher risk for idiopathic proteinuric podocytopathies.
• This increased risk is partly attributed to specific risk alleles within the APOL1 gene.
• The precise pathogenic mechanisms linking APOL1 risk alleles to kidney disease remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying APOL1-associated nephropathy.
• To analyze glomerular transcriptomes and identify gene expression patterns associated with APOL1 risk alleles in patients with idiopathic nephrotic syndrome.
• To explore the relationship between APOL1 risk alleles, gene coexpression networks, and clinical outcomes, particularly in individuals with African ancestry.

Main Methods:

• Analysis of glomerular RNA sequencing (RNASeq) transcriptomes from patients with idiopathic nephrotic syndrome, stratified by inferred African ancestry (AA) and non-African ancestry (noAA).
• Utilized gene coexpression network analysis to identify modules associated with APOL1 risk allele number.
• Employed Characteristic Direction (ChDir) to identify gene signatures differentiating patients based on APOL1 genotype and assessed associations with clinical outcomes (remission, kidney failure, eGFR decline).

Main Results:

• A significant association was found between the number of APOL1 risk alleles and a specific coexpression module (MM2), independent of eGFR and proteinuria.
• In patients with African ancestry, higher activation scores of MM2 and a 1481-gene signature identified by ChDir correlated with lower rates of complete remission and a trend towards faster kidney function decline.
• MM2 and ChDir gene signatures were enriched for epithelial-mesenchymal transition and inflammation pathways and significantly overlapped with parietal epithelial cell (PEC) identity genes, but not podocyte genes.

Conclusions:

• APOL1 risk alleles are associated with distinct gene expression patterns in the glomerulus, characterized by inflammation and epithelial-mesenchymal transition signatures.
• These findings suggest that podocytes expressing variant APOL1 may release inflammatory signals that activate PECs, contributing to the pathogenesis of APOL1 nephropathy.
• The identified gene signatures and pathways provide novel insights into the mechanisms driving differential susceptibility to kidney disease in individuals with African ancestry carrying APOL1 risk alleles.