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

• DOI: 10.1111/jdi.13311
• Publication Date: 2020-05-30T08:19:03Z
• Authors: Yuiko Mizunuma; Keizo Kanasaki; Kyoko Nitta; Yuka Nakamura; Yasuhito Ishigaki; Yuta Takagaki; Munehiro Kitada; Shaolan Li; Haijie Liu; Jinpeng Li; Isao Usui; Yoshimasa Aso; Daisuke Koya
• Keywords: Male; 0303 health sciences; Articles; RC648-665; Fibrosis; Diseases of the endocrine glands. Clinical endocrinology; Diabetes Mellitus, Experimental; Disease Models, Animal; Mice; 03 medical and health sciences; Gene Expression Regulation; N‐acetyl‐seryl‐aspartyl‐lysyl‐proline; Disease Progression; Animals; Diabetic Nephropathies; Diabetic kidney disease

AbstractAims/IntroductionTo 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 MethodsWe 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.ResultsMale 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.ConclusionsThese results suggest that CD‐1db/db mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.