The Dual Endothelin Angiotensin Receptor Antagonist (DEARA) Sparsentan Protects from Glomerular Hypercellularity and Associated Immune/Inflammatory Gene Network Activity in a Model of IgA Nephropathy

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Background: IgA Nephropathy (IgAN) is an autoimmune glomerulonephritis wherein immune complexes (IC) composed of galactose-deficient IgA1 (Gd-IgA1; autoantigen) and Gd-IgA1-specific IgG autoantibodies (AuAb) deposit in the glomeruli (gli) and cause injury. In a mouse model of IgAN induced by IC formed in vitro from human Gd-IgA1 and a recombinant AuAb, we used whole-kidney RNAseq profiling to assess how Sparsentan (Sp) affects the gene expression of pathways dysregulated by IC. Methods: IC were injected into ˜7-week-old nude mice every other day for a total of 6 doses (n=5/group). Sp (60 or 120 mg/kg) or vehicle (V) were given by gavage once daily from the first day of IC injections. Negative-control mice received only V. Kidney tissue for histopathology and RNAseq was harvested on day 12. RNAseq raw data processed using DESeq2 identified differentially expressed genes. WGCNA was used for network-level profiling and to identify co-expressed genes associated with hypercellularity and Ki-67 positivity of gli. GSEA and X2K assessed changes at the pathway level and imputed correlated upstream cell-signaling networks. Pathway enrichment p-values were adjusted with FDR. Results: Sp ameliorated IC-induced hypercellularity (P<0.01) and Ki-67-positive gli (P<0.05). WGCNA clustered genes into co-expressed modules associated with hypercellularity and Ki-67 positivity. GSEA-identified top-5 pathways were enriched for immune processes (FDR <1x10ˆ-20), the top being cytokine signaling pathways. The expression pattern of 95% of the top module genes dysregulated by IC, was corrected by Sp. X2K analysis revealed correlated expression of top hub genes, kinases MAPK14, GSK3B, CSNK2A1 (z-score <1x10ˆ-12) and transcription factors SP1 and RUNX1 (z-score <0.05), highlighting the role of the ERK1/2-SP1 axis known to regulate cell proliferation. Conclusions: In a mouse model of IgAN, kidney transcriptomics revealed gene networks, enriched in immune/inflammatory functions, correlating with IC-induced hypercellularity. The top dysregulated genes were normalized by Sp and were linked to kinases and transcription factors with correlated functional activity. These data suggest a potential anti-inflammatory role for Sp in IgAN. Funding: Commercial Support - Travere Therapeutics, Inc., San Diego, CA

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