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.