Renin is critical for Renin Lineage Cell Plasticity and Migration in experimental crescentic Glomerulonephritis

Key Points Renin deficiency in renin-lineage cells worsened crescentic injury and impaired cell migration, revealing a protective role for renin in crescentic glomerulonephritis. Loss of renin shifted renin-lineage cells signaling toward interferon/STAT1-driven Renin-lineage cell ablation in crescentic glomerulonephritis induced a less inflammatory disease time-course.

The adult juxtaglomerular renin-lineage cell (RLC) niche contributes to intraglomerular repair after injury, but their role in highly inflammatory crescentic glomerulonephritis (cGN) remains unclear. While angiotensin II–AT1R signaling promotes fibrosis and inflammation, the contribution of the RLCs, and of renin expression within RLCs, to cGN outcome has not been investigated.

We used tdTomato lineage-tracing to track RLCs in wild-type (WT) and renin-knockout (RenKO) mice following cGN induction. RLC migration and glomerular injury were quantified histologically. Single-cell RNA sequencing was performed on isolated tdTomato-positive 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) RLC ablation.

RLCs were detected within injured glomeruli during cGN, with sporadic localization to crescentic lesions. Genetic renin deletion in RLCs worsened cGN outcomes, with RenKO mice developing increased albuminuria (by 306%), crescent formation (by 50%) and podocyte loss (by 15%) by day 21 compared to WT controls. Renin-deficient RLCs exhibited a reduced intraglomerular migratory response with decreased colocalization with mesangial and podocytes cell markers. Single-cell transcriptomic analysis supports an immunomodulatory reparative phenotype in WT RLCs. In contrast, RenKO RLCs displayed enrichment of interferon-stimulated genes and pathways suppressing cell migration. RLC ablation reduced macrophage infiltration, but did not alter disease progression, suggesting compensatory cellular mechanisms.

Renin expression supports the plasticity and injury-associated responses of RLCs during cGN. Loss of renin shifts RLCs toward an interferon-driven inflammatory and antimigratory phenotype that aggravates glomerular injury, while ablation of the RLCs may be compensated without major outcome changes. Competing Interest Statement The authors have declared no competing interest.