Effects of Anti-GBM Serum on Kidney Function and Glomerulosclerosis in Mice

Background: Antibody-induced glomerulonephritis (GN) is a condition characterized by an inappropriate autoimmune response to renal antigens, such as glomerular basement membrane (GBM), leading to progressive glomerulosclerosis and rapidly declining renal failure, for which few treatment options exist. Understanding the underlying mechanisms of GN is crucial for developing effective therapeutic strategies. In this study, our objective was to investigate the induction of antibody-induced GN using anti-GBM serum on kidney biomarkers, histology and transcriptome signatures. Methods: Male C57BL/6J mice (n=12) were randomly assigned to three groups (n=4 per group) and received an injection of vehicle, 100, or 200 μl of anti-GBM serum. We measured urinary albumin-creatinine ratio (ACR) as an indicator of kidney function. Renal endpoints included urinary albumin-creatinine ratio (ACR), AI-assisted glomerulosclerosis score, histology analysis of fibrosis (Collagen type 3, Col3), and RNA sequencing (RNA-seq) analysis. Results: Compared with vehicle controls, both doses of anti-GBM serum significantly increased urinary ACR, suggesting renal insufficiency and glomerular damage. AI-based histopathological scoring confirmed significant glomerulosclerosis increase in the anti-GBM serum-treated groups. Furthermore, IHC image analysis indicated renal fibrotic damage as shown by the increase of Col3. Consistent with this, RNA-seq analysis revealed upregulated gene expression programs indicative of kidney extracellular matrix remodelling (eg, Col1a1, Col3a1, Col4a1) and inflammation (eg, CD68, Ccl2, Il1b). Conclusion: Anti-GBM serum induces the rapid onset of renal failure, glomerulosclerosis, and fibrosis in the murine model of antibody-induced GN. The antibody-induced GN model in mice is very useful for testing test compounds with potential nephroprotective effects in autoimmune GN. Funding: Commercial Support - Gubra