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Updated: Nov 1, 2025
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations
Hui Song1, Mingchao Zhang1, Xue Li1
1National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Insights
C3 glomerulopathy (C3GP) is linked to complement alternative pathway (AP) abnormalities. A new mouse model reveals that complement factor I (CFI) D288G variations can cause C3 deposition, a key feature of C3GP, especially when mimicking infection.
Area of Science:
- Nephrology
- Immunology
- Genetics
Background:
- C3 glomerulopathy (C3GP) is a kidney disease characterized by abnormal complement alternative pathway (AP) activity and C3 deposition in glomeruli.
- Genetic variations in complement factors are suspected contributors to C3GP, but experimental validation is limited.
- A patient with C3 glomerulonephritis (C3GN) and compound heterozygous novel complement factor I (CFI) variations was previously reported.
Purpose of the Study:
- To create and analyze a mouse model mimicking human complement factor I (CFI) variations.
- To investigate the pathogenicity of CFI variations in the development of C3 glomerulonephritis (C3GN).
- To establish a tool for studying triggers of C3GN.
Main Methods:
- Utilized CRISPR/Cas9 gene editing to generate mouse lines with specific CFI mutations (D288G and P467S).
- Created compound heterozygous mice for CFI D288G and P467S.
- Administered lipopolysaccharides (LPS) to mice to simulate infection/sepsis and assessed kidney function, albuminuria, and C3 deposition.
Main Results:
- Mice with compound heterozygous CFI D288G and P467S variations showed normal phenotypes without LPS treatment.
- LPS challenge induced albuminuria, impaired kidney function, and C3 glomerular deposition in these mice.
- Unexpectedly, CFI D288G homozygotes developed severe mesangial C3 deposition in the LPS model, implicating this CFI variation in C3GN pathogenesis.
Conclusions:
- The generated mouse models are valuable for studying the role of CFI variations in C3GN development.
- The CFI D288G variation is identified as a contributor to C3 deposition in a model mimicking infection.
- These mouse lines can aid in screening environmental factors and infections that may trigger C3GN.
Abstract:
C3 glomerulopathy (C3GP) is a disease entity caused by abnormality of the complement alternative pathway (AP) and characterized by C3 deposition in glomeruli. Many variations or mutations of complement factors are believed to underlie the susceptibility to C3GP, but there is a lack of experimental evidence. We have recently reported a patient with C3 glomerulonephritis (C3GN) and compound heterozygosity of two novel variations in the complement factor (CFI). Here, we generated a mouse model to mimic the CFI variations for studying pathogenicity of CFI variations in C3GN development. We used the CRISPR/Cas9 system to make mutant mouse lines that carried D288G and P467S mutations in CFI, respectively, and crossed them to generate mice with compound heterozygosity of CFI D288G and P467S. The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, we found that the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN. The mouse lines generated in the present study can be used to further study the role of CFI variations in C3GN development; in addition, they may be used to screen and test infections and environmental factors capable of triggering C3GN.
