Journal
JOURNAL OF DIABETES INVESTIGATION
Volume 11, Issue 6, Pages 1470-1481Publisher
WILEY
DOI: 10.1111/jdi.13311
Keywords
Diabetic kidney disease; Fibrosis; N-acetyl-seryl-aspartyl-lysyl-proline
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Funding
- Japan Society for the Promotion of Science [19K08738, 26460403, 25282028, 25670414]
- Kanazawa Medical University [S2016-3, S2017-1, K2017-16]
- Grants-in-Aid for Scientific Research [19K08738] Funding Source: KAKEN
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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 (BKSdb/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 thedbgene 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 beta 4, was significantly lower in the CD-1 mice. Thymosin beta 4 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.
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