A Human Glomerular Disease Atlas defines the APOL1-JAK-STAT feed forward loop in focal segmental glomerulosclerosis

There are few approved treatments for glomerular diseases of the kidney. To map underlying transcriptional programs in the kidney driving rare glomerular diseases, single-nucleus RNA sequencing (snRNAseq) on kidney biopsies (N=120) from the Nephrotic Syndrome Study Network were integrated with snRNAseq and single-cell sequencing (scRNAseq) of reference kidney tissue (N=50) to create the Omnibus of CElls And Nuclei (OCEAN). Unsupervised analysis of multi-cellular programs identified that JAK-STAT pathway activity was associated with clinical measures of disease severity. JAK-STAT pathway activity was strongly correlated with apolipoprotein1 (APOL1) mRNA transcript expression and the high risk APOL1 variant genotype, a major risk factor for focal segmental glomerulosclerosis. These findings were confirmed in an independent study of Black participants where loss of APOL1 function decreased JAK-STAT pathway activation in ex vivo models of patient-derived podocytes. The findings presented are consistent with a feed forward loop regulating the JAK-STAT-APOL1 driven tissue damage, providing mechanistic support for the JUSTICE Phase II trial targeting JAK activation in APOL1-mediated kidney disease.