CD-1^db/db mice: A novel type 2 diabetic mouse model with progressive kidney fibrosis

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 (BKS^{db / db} ) is often utilized for diabetic kidney disease research; the kidney fibrosis in the BKS^{db / db} phenotype is minimal.

Materials and methods: We generated CD-1^{db / db} mice by backcrossing the db gene into the CD-1 background, and analyzed phenotypic differences compared with BKS^{db / db} and CD-1^{db / m} mice.

Results: Male CD-1^{db / db} mice appeared to have elevated blood glucose levels compared with those of BKS^{db / db} mice. Fasting insulin levels declined in CD-1^{db / db} mice. Plasma cystatin C levels tended to be elevated in CD-1^{db / db} mice from 16 to 24 weeks-of-age. Male CD-1^{db / db} mice showed significantly progressive kidney and heart fibrosis from 16 to 24 weeks-of-age when compared with that of age-matched BKS^{db / db} mice. The gene expression profile showed fibrogenic program-associated genes in male CD-1^{db / db} mice. Male CD-1^{db / db} mice displayed significantly lower urine antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline when compared to that of BKS^{db / 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-1^{db / db} mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.