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

Methods: A human C3 transgene was introduced into B6 mouse embryos to generate B6-hC3 mice. Additionally, the endogenous mouse C3 gene in B6-hC3 mice was knocked out to generate B6-hC3 mC3 KO mice. Both B6-hC3 and B6-hC3 mC3 KO mice were evaluated longitudinally for renal dysfunction via urinalysis. RNA sequencing (RNA-seq) was performed on both B6-hC3 and B6-hC3 mC3 KO mice to identify differentially expressed genes and pathways between strains and sexes.

Results: Both B6-hC3 and B6-hC3 mC3 KO strains developed hallmark features of C3G. However, B6-hC3 mC3 KO mice exhibited more severe renal dysfunction and damage compared to B6-hC3. Notably, female B6-hC3 mC3 KO mice developed higher levels of proteinuria and exhibit diverse renal lesions compared to males, suggesting sex-specific susceptibility. RNA-seq analysis revealed strain-specific transcriptomic profiles between B6-hC3 and B6-hC3 mC3 KO strains, as well as sex-associated gene expression signatures between male and female B6-hC3 mC3 KO mice.

Conclusion: In this study, two novel humanized mouse models that recapitulate key features of human C3G were established. Phenotypic and transcriptomic analyses reveal critical differences between strains and sex, making these models valuable platforms for future mechanistic studies of C3G and for the preclinical evaluation of targeted complement-modulating therapies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phenotypic-and-transcriptomic-divergence-in-c3-glomerular-mouse-models-insights-into-immune-and-sex-correlates/