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Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
CD-1db/db mice: A novel type 2 diabetic mouse model with progressive kidney fibrosis
Yuiko Mizunuma1,2, Keizo Kanasaki1,3,4, Kyoko Nitta1
1Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
Aims/Introduction:
To establish novel therapies to combat diabetic kidney disease, a human disease-relevant animal model is essential. However, a type 2 diabetic mouse model presenting progressive kidney fibrosis has not yet been established. Kidneys of streptozotocin-induced diabetic CD-1 mice showed severe fibrosis compared with other backgrounds of mice associated with the suppression of antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline. The BKS background (BKSdb / db ) is often utilized for diabetic kidney disease research; the kidney fibrosis in the BKSdb / db phenotype is minimal.
Materials And Methods:
We generated CD-1db / db mice by backcrossing the db gene into the CD-1 background, and analyzed phenotypic differences compared with BKSdb / db and CD-1db / m mice.
Results:
Male CD-1db / db mice appeared to have elevated blood glucose levels compared with those of BKSdb / db mice. Fasting insulin levels declined in CD-1db / db mice. Plasma cystatin C levels tended to be elevated in CD-1db / db mice from 16 to 24 weeks-of-age. Male CD-1db / db mice showed significantly progressive kidney and heart fibrosis from 16 to 24 weeks-of-age when compared with that of age-matched BKSdb / db mice. The gene expression profile showed fibrogenic program-associated genes in male CD-1db / db mice. Male CD-1db / db mice displayed significantly lower urine antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline when compared to that of BKSdb / db at 24 weeks-of-age. The gene expression of prolyl oligopeptidase, the enzyme essential for antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline production from thymosin β4, was significantly lower in the CD-1 mice. Thymosin β4 levels were also lower in CD-1 mice.
Conclusions:
These results suggest that CD-1db / db mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.
Insights
A novel mouse model, CD-1db / db mice, exhibits progressive kidney and heart fibrosis, crucial for studying type 2 diabetic kidney disease. This model shows suppressed antifibrotic peptide production, offering new therapeutic avenues.
Area of Science:
- Nephrology
- Diabetology
- Animal Models
Background:
- Diabetic kidney disease (DKD) requires human-relevant animal models for novel therapy development.
- Existing type 2 diabetic mouse models, like BKSdb / db, exhibit minimal kidney fibrosis.
- CD-1 mice treated with streptozotocin show fibrosis linked to suppressed antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline.
Purpose of the Study:
- To establish a novel type 2 diabetic mouse model with progressive kidney fibrosis for DKD research.
- To characterize the phenotypic differences of CD-1db / db mice compared to BKSdb / db mice.
Main Methods:
- Generation of CD-1db / db mice through genetic backcrossing.
- Phenotypic analysis including blood glucose, insulin, plasma cystatin C, and fibrosis assessment in kidneys and hearts.
- Gene expression profiling and measurement of antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline and related enzymes.
Main Results:
- CD-1db / db mice exhibited elevated blood glucose and declining insulin levels.
- Progressive kidney and heart fibrosis was observed in male CD-1db / db mice from 16 to 24 weeks.
- Suppressed antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline and lower thymosin β4 levels were noted in CD-1 mice.
Conclusions:
- CD-1db / db mice represent a novel and valuable model for type 2 diabetic kidney disease research.
- The model's progressive fibrosis and altered antifibrotic pathways offer insights into DKD pathogenesis.
- This model is suitable for evaluating new therapeutic strategies against diabetic kidney and heart fibrosis.
