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

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 ) is often utilized for diabetic kidney disease research; the kidney fibrosis in the BKS phenotype is minimal. We generated CD-1 mice by backcrossing the db gene into the CD-1 background, and analyzed phenotypic differences compared with BKS and CD-1 mice. Male CD-1 mice appeared to have elevated blood glucose levels compared with those of BKS mice. Fasting insulin levels declined in CD-1 mice. Plasma cystatin C levels tended to be elevated in CD-1 mice from 16 to 24 weeks-of-age. Male CD-1 mice showed significantly progressive kidney and heart fibrosis from 16 to 24 weeks-of-age when compared with that of age-matched BKS mice. The gene expression profile showed fibrogenic program-associated genes in male CD-1 mice. Male CD-1 mice displayed significantly lower urine antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline when compared to that of BKS 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. These results suggest that CD-1 mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.