Renin Is Critical for Renin Lineage Cell Plasticity, Migration, and Disease Outcome in Experimental Crescentic Glomerulonephritis

Background: The adult juxtaglomerular renin-lineage cell niche demonstrates cellular plasticity following injury, but its role in highly inflammatory crescentic glomerulonephritis (crescentic GN) remains unclear. While renin-angiotensin signaling promotes fibrosis and inflammation, the contribution of the renin-lineage cells and renin expression within these cells to crescentic GN has not been investigated. Methods: We used tdTomato (tdT) lineage-tracing to track renin-lineage cells in wild-type (WT) and renin-knockout (RenKO) mice following crescentic GN induction. Renin-lineage cell migration and glomerular injury were quantified histologically. Single-cell RNA sequencing was performed on isolated tdT+ cells at day 10 and 21 after injury to characterize transcriptional programs. Disease progression was additionally examined in mice with diphtheria toxin A–mediated (DTA) renin-lineage cell ablation. Results: Renin-lineage cells were detected within injured glomeruli during crescentic GN. Genetic renin deletion worsened disease outcomes, with RenKO mice developing increased albuminuria (by 3-fold), crescent formation (by 50%) and podocyte loss (by 15%) by day 21 compared to WT controls. Renin-deficient renin-lineage cells exhibited reduced glomerular migration and decreased colocalization with mesangial cell markers. Single-cell transcriptomic analysis revealed distinct transcriptional programs between WT and RenKO renin-lineage cells, with RenKO cells enriched for interferon-stimulated and reduced migration-associated pathways. Renin-lineage cell ablation reduced macrophage infiltration, but did not alter disease severity. Conclusions: Renin expression influenced migration and injury-associated responses of renin-lineage cells during crescentic GN. Loss of renin was associated with a dysfunctional interferon-driven and anti-migratory phenotype together with more severe glomerular injury, whereas renin-lineage cell ablation reduced macrophage infiltration but had limited effects on overall disease severity.