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

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

doi:10.1111/jdi.13311

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

J Diabetes Investig. 2020 Nov;11(6):1470-1481. doi: 10.1111/jdi.13311. Epub 2020 Jul 3.

Authors

Yuiko Mizunuma^{1

2}, Keizo Kanasaki^{1

3

4}, Kyoko Nitta¹, Yuka Nakamura⁵, Yasuhito Ishigaki⁵, Yuta Takagaki¹, Munehiro Kitada^{1

3}, Shaolan Li¹, Haijie Liu¹, Jinpeng Li¹, Isao Usui², Yoshimasa Aso², Daisuke Koya^{1

3}

Affiliations

¹ Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
² Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan.
³ Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
⁴ Internal Medicine 1, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
⁵ Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.

Abstract

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.

Keywords: Diabetic kidney disease; Fibrosis; N-acetyl-seryl-aspartyl-lysyl-proline.

MeSH terms

Animals
Diabetes Mellitus, Experimental / complications*
Diabetic Nephropathies / etiology
Diabetic Nephropathies / metabolism
Diabetic Nephropathies / pathology*
Disease Models, Animal*
Disease Progression
Fibrosis / etiology
Fibrosis / metabolism
Fibrosis / pathology*
Gene Expression Regulation*
Male
Mice

Abstract

MeSH terms

Grants and funding