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Development and Characterization of a Novel FVB-Prkdc Mouse Model for Adriamycin-Induced Nephropathy
Masaki Watanabe1, Yuki Ishii1, Kazuki Hashimoto1
1Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Towada 034-8628, Japan.
Abstract:
The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the Prkdc polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of ADR nephropathy in the FVB/N strain has yet to be conducted. Our research aimed to create a novel mouse model, the FVB-Prkdc, by introducing Prkdc into the FVB/NJcl (FVB) strain. Our study showed that FVB-Prkdc mice developed severe renal damage when exposed to ADR, as evidenced by significant albuminuria and tubular injury, exceeding the levels observed in C57BL/6J (B6)-Prkdc. This indicates that the FVB/N genetic background, in combination with the R2140C mutation, strongly predisposes mice to ADR nephropathy, highlighting the influence of genetic background on disease susceptibility. Using RNA sequencing and subsequent analysis, we identified several genes whose expression is altered in response to ADR nephropathy. In particular, Mmp7, Mmp10, and Mmp12 were highlighted for their differential expression between strains and their potential role in influencing the severity of kidney damage. Further genetic analysis should lead to identifying ADR nephropathy modifier gene(s), aiding in early diagnosis and providing novel approaches to kidney disease treatment and prevention.
Insights
Researchers developed a new mouse model, FVB-Prkdc, to study Adriamycin (ADR) nephropathy. This model, susceptible to kidney damage, helps understand genetic influences on ADR-induced kidney disease.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Adriamycin (ADR) nephropathy is a key model for podocyte injury.
- Genetic factors, like the Prkdc polymorphism, influence ADR nephropathy susceptibility.
- The FVB/N mouse strain typically resists ADR nephropathy due to the absence of the R2140C mutation.
Purpose of the Study:
- To create and characterize a novel FVB-Prkdc mouse model for ADR nephropathy.
- To investigate the impact of the FVB/N genetic background combined with the Prkdc R2140C mutation on ADR-induced kidney damage.
- To identify genes differentially expressed in response to ADR nephropathy.
Main Methods:
- Introduction of the Prkdc gene into the FVB/NJcl (FVB) mouse strain to create the FVB-Prkdc model.
- Administration of Adriamycin (ADR) to FVB-Prkdc and C57BL/6J (B6)-Prkdc mice.
- Assessment of renal damage through albuminuria and tubular injury measurements.
- RNA sequencing and gene expression analysis.
Main Results:
- FVB-Prkdc mice exhibited severe renal damage, including significant albuminuria and tubular injury, upon ADR exposure.
- Renal damage in FVB-Prkdc mice exceeded that observed in B6-Prkdc mice, indicating a strong genetic predisposition.
- RNA sequencing identified altered expression of genes, including Mmp7, Mmp10, and Mmp12, potentially linked to kidney damage severity.
Conclusions:
- The FVB/N genetic background significantly enhances susceptibility to ADR nephropathy when combined with the Prkdc R2140C mutation.
- The novel FVB-Prkdc mouse model is valuable for studying ADR-induced kidney disease.
- Identifying differentially expressed genes like Mmp7, Mmp10, and Mmp12 may offer insights into kidney disease mechanisms and therapeutic targets.
