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Kidney Week

Abstract: TH-PO549

Identifying Targetable Renal Immune Pathways in Lupus Nephritis

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Bhandari, Aneesha, University of Oxford, Oxford, United Kingdom
  • Cornall, Richard John, University of Oxford, Oxford, United Kingdom
  • Bull, Katherine R., University of Oxford, Oxford, United Kingdom
Background

Lupus Nephritis (LN) is characterised by renal immune-complex (IC) deposition, how these deposits trigger inflammatory mediators, and signalling between resident and recruited cells is unclear. Mouse lupus models share clinical features of human disease including renal involvement. Using single nuclei RNA sequencing (snRNA-seq), we compare two models of early LN, to identify disease drivers, potential therapeutic targets, and to establish an approach translatable to human kidney.

Methods

Kidney sections from autoimmune MRL/lpr mice aged 15-weeks, or Balb/c mice treated for 8 weeks with topical TLR7 agonist (IMQ) and respective controls, were processed for histology, immunofluorescence (IF), flow cytometry and snRNA-seq (10x genomics).

Results

IMQ kidneys showed IC deposition, mesangial expansion, and endothelial proliferation consistent with class-II LN. MRL/lpr mice additionally developed crescents, and class-III LN. Transcriptomic data from 92k nuclei identified clusters corresponding to resident and immune populations. Early S1/S2 proximal tubule segments were identified as interferon (IFN) susceptible targets in both models. Intrarenal T, B, and myeloid cells were enriched in diseased mice. MRL/lpr mice had the largest immune infiltrate, including NK and CD8 T cells expressing markers of cytotoxicity and exhaustion (Gzma, Pdcd1). Integrated analysis with human immune renal LN single cell data (Arazi et al., 2019), showed overlap with MRL/lpr phenotype with cytotoxicity and exhaustion signatures (GZMA, PDCD1) identified in the NK and CD8 T cell clusters. Shared disease phenotypes across models included increased CD11bhi renal resident macrophage populations, expressing genes implicated in phagocytosis, efferocytosis (Mertk, Lrp1) and IFN responses (Stat1), with trajectory analysis suggesting these arise from increased patrolling non-classical monocytes, and highlighting targets to inhibit monocyte infiltration.

Conclusion

Integrated kidney snRNA-seq in two LN models delineates a shared immune signature, with interactions with stromal, tubular, and glomerular cells important in early disease perpetuation and damage. Our comprehensive kidney single nuclei approach is generalisable, suggests candidate genes for rescue experiments and can be applied to human renal tissue.