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Kidney Week

Abstract: FR-PO707

Anti-Glomerular Basement Membrane (GBM) Serum Effects on Kidney Function and Glomerulosclerosis in Mice

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Frias Hernandez, Alex, Gubra, Horsholm, Denmark
  • Secher, Thomas, Novo Nordisk A/S, Bagsvaerd, Denmark
  • Marstrand-Jørgensen, Adam Bøgh, Gubra, Horsholm, Denmark
  • Sembach, Frederikke Emilie, Gubra, Horsholm, Denmark
  • Ougaard, Maria Katarina, Gubra, Horsholm, Denmark
  • Hansen, Henrik H., Gubra, Horsholm, Denmark
  • Christensen, Michael, Gubra, Horsholm, Denmark
Background

Antibody-induced glomerulonephritis (GN) is a condition characterized by caused by an inappropriate autoimmune response to renal antigens, such as the glomerular basement membrane (GBM), leading to progressive glomerulosclerosis and rapidly declining renal dysfunction for which there exist only few treatment options. Understanding the underlying mechanisms of GN is crucial for developing effective therapeutic strategies. In this study, we aimed to investigate the induction of antibody-induced GN by anti-GBM serum on kidney biomarkers, histology and transcriptome signatures.

Methods

Male C57BL/6J mice (n=15) were randomized into three groups (n=5 per group) and received either vehicle injection, 100, or 200 µl of anti-GBM serum. We measured urine albumin-to-creatinine ratio (ACR) as an indicator of renal function. Renal endpoints included urine albumin-to-creatinine ratio (ACR), AI-assisted glomerulosclerosis scoring, histomorphometric analysis of fibrosis (Col3a1), and RNA sequencing (RNA-seq) analysis.

Results

Compared to vehicle controls, both doses of anti-GBM serum significantly increased urine ACR, indicating renal dysfunction and glomerular injury. AI-assisted based histopathological scoring confirmed significant glomerulosclerosis in anti-GBM serum-treated groups. Additionally, IHC image analysis indicated renal fibrotic injury. Correspondingly, RNA-seq analysis revealed upregulated gene expression programs signifying renal extracellular matrix remodelling (e.g., Col1a1, Col3a1, Col4a1) inflammation (e.g., CD68, Ccl2, Il1b).

Conclusion

Anti-GBM serum induces fast onset of renal dysfunction, glomerulosclerosis, and fibrosis in the mouse model of antibody-induced GN. The antibody-induced GN model in mice is highly applicable for probing test compounds with potential nephroprotective effects autoimmune GN.

Funding

  • Commercial Support – Gubra