{"doi":"10.1101/2025.09.12.25335572","title":"A Human Glomerular Disease Atlas defines the APOL1-JAK-STAT feed forward loop in focal segmental glomerulosclerosis","abstract":"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.","journal":"medRxiv","year":2025,"id":555747,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":35.0,"corpus_rank":8395,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.6157,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1454574,"name":"Charlotte Boys","orcid":"0000-0003-3955-5110","position":1,"is_corresponding":false},{"id":1207859,"name":"Somenath Datta","orcid":null,"position":2,"is_corresponding":false},{"id":29419,"name":"Viji Nair","orcid":"0000-0003-1657-954X","position":3,"is_corresponding":false},{"id":255141,"name":"Edgar A. 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