2025/09/14 by Phillip J. McCown, Charlotte Boys, Somenath Datta +26 · 1 voice · 1 citation
Medicine · Biochemistry, Genetics and Molecular Biology · #Renal Diseases and Glomerulopathies #Renal and related cancers #Genetic Syndromes and Imprinting
paper · pdf · doi:10.1101/2025.09.12.25335572
openalex publication_date 2025/09/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Abstract 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.