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Updated: Nov 26, 2025
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy
Kishor Devalaraja-Narashimha1, Karoline Meagher, Yifan Luo
1Regeneron Pharmaceuticals, Tarrytown, New York.
Insights
A new humanized C3 mouse model rapidly develops C3 glomerulopathy (C3G), mirroring human disease pathology. This model accelerates C3G research and therapeutic testing for kidney disease.
Area of Science:
- Nephrology
- Immunology
- Genetics
Background:
- C3 glomerulopathy (C3G) involves alternative complement pathway (AP) hyperactivation.
- Current mouse models for C3G progress slowly, limiting research.
- Novel models are crucial for understanding C3G mechanisms and treatments.
Purpose of the Study:
- To develop and characterize a novel, rapidly progressing murine model of C3G.
- To utilize this model for evaluating therapeutic interventions.
Main Methods:
- Humanized C3 (C3hu/hu) mice were created using VelociGene technology.
- Functional, histologic, and molecular assays were employed.
- Pharmacologic interventions were tested in the C3hu/hu model.
Main Results:
- C3hu/hu mice exhibited early morbidity and mortality (5-6 months).
- Key C3G biomarkers (glomerulosclerosis, C3/C5b-9 deposition) were elevated.
- C5 or AP blockade improved survival and kidney function.
Conclusions:
- C3hu/hu mice serve as a valuable C3G model, sharing human disease features.
- The model's accelerated course aids preclinical therapeutic assessment.
- Dysregulated human C3 interaction with mouse complement proteins likely drives the phenotype.
Background:
C3 glomerulopathy (C3G) is characterized by the alternative-pathway (AP) hyperactivation induced by nephritic factors or complement gene mutations. Mice deficient in complement factor H (CFH) are a classic C3G model, with kidney disease that requires several months to progress to renal failure. Novel C3G models can further contribute to understanding the mechanism behind this disease and developing therapeutic approaches.
Methods:
A novel, rapidly progressing, severe, murine model of C3G was developed by replacing the mouse C3 gene with the human C3 homolog using VelociGene technology. Functional, histologic, molecular, and pharmacologic assays characterize the presentation of renal disease and enable useful pharmacologic interventions in the humanized C3 (C3hu/hu) mice.
Results:
The C3hu/hu mice exhibit increased morbidity early in life and die by about 5-6 months of age. The C3hu/hu mice display elevated biomarkers of kidney dysfunction, glomerulosclerosis, C3/C5b-9 deposition, and reduced circulating C3 compared with wild-type mice. Administration of a C5-blocking mAb improved survival rate and offered functional and histopathologic benefits. Blockade of AP activation by anti-C3b or CFB mAbs also extended survival and preserved kidney function.
Conclusions:
The C3hu/hu mice are a useful model for C3G because they share many pathologic features consistent with the human disease. The C3G phenotype in C3hu/hu mice may originate from a dysregulated interaction of human C3 protein with multiple mouse complement proteins, leading to unregulated C3 activation via AP. The accelerated disease course in C3hu/hu mice may further enable preclinical studies to assess and validate new therapeutics for C3G.
