Phenotypic and Transcriptomic Divergence in C3 Glomerular Mouse Models: Insights into Immune and Clinical Sex Correlates

Complement component C3 is central to the alternative pathway (AP) and plays a key role in the pathogenesis of C3 glomerulopathy (C3G), a rare renal disease characterized by complement dysregulation. To model human-specific complement activity, we developed two humanized C3 mouse models: B6-hC3 (expressing a human C3 transgene) and B6-hC3 mC3 KO (expressing a human C3 transgene with knockout of mouse C3). These models were designed to promote unregulated C3 activation of the alternative pathway (AP) and reproduce C3G-like phenotypes. Through longitudinal phenotyping and RNA sequencing, we sought to elucidate molecular mechanisms underlying disease development and investigate sex-associated gene expression signatures.