Weigang Luo1, Yijin Yu1, Hao Wang2, Kun Liu2, Yu Wang1, Minling Huang1, Chenhao Xuan1, Yanning Li3, Jinsheng Qi4,5. 1. Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China. 2. Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China. 3. Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China. liyanning1981@126.com. 4. Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China. qijinsheng777@163.com. 5. Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, People's Republic of China. qijinsheng777@163.com.
Abstract
AIMS: Besides energy supply, β-hydroxybutyrate (BHB) acts as a bioactive molecule to play multiple protective roles, even in diabetes and its complications. The aim of this study was to investigate the antagonizing effects of BHB against diabetic glomerulosclerosis and the underlying mechanism. METHODS: Male Sprague-Dawley rats were intraperitoneally injected with streptozotocin to induce diabetes and then treated with different concentrations of β-hydroxybutyrate. After 10 weeks, body weight, blood glucose, serum creatinine and 24-h urine protein were examined. Glomerular morphological changes and the contents of collagen type IV (COL IV) were evaluated. Then, transforming growth factor (TGF)-β/Smad3 contents and matrix metalloproteinase-2 (MMP-2) generation were detected. Moreover, the total contents of trans-activating histone H3K9 β-hydroxybutyrylation (H3K9bhb) and the contents of H3K9bhb in the Mmp-2 promoter were measured. RESULTS: It was firstly confirmed that BHB treatments reduced renal biochemical indicators and attenuated glomerular morphological changes of the diabetic rats, with COL IV content decreased in a concentration-dependent manner. Then, BHB treatments were found to up-regulate renal MMP-2 generation of the diabetic rats significantly, while not affecting the increased TGF-β/Smad3 contents. Furthermore, the contents of H3K9bhb in the Mmp-2 promoter were elevated significantly for the middle and high concentrations of BHB treatments, up-regulating MMP-2 generation. CONCLUSION: BHB treatments could up-regulate MMP-2 generation via causing elevated H3K9bhb in its promoter to antagonize glomerulosclerosis in the diabetic rats.
AIMS: Besides energy supply, β-hydroxybutyrate (BHB) acts as a bioactive molecule to play multiple protective roles, even in diabetes and its complications. The aim of this study was to investigate the antagonizing effects of BHB against diabetic glomerulosclerosis and the underlying mechanism. METHODS: Male Sprague-Dawley rats were intraperitoneally injected with streptozotocin to induce diabetes and then treated with different concentrations of β-hydroxybutyrate. After 10 weeks, body weight, blood glucose, serum creatinine and 24-h urine protein were examined. Glomerular morphological changes and the contents of collagen type IV (COL IV) were evaluated. Then, transforming growth factor (TGF)-β/Smad3 contents and matrix metalloproteinase-2 (MMP-2) generation were detected. Moreover, the total contents of trans-activating histone H3K9 β-hydroxybutyrylation (H3K9bhb) and the contents of H3K9bhb in the Mmp-2 promoter were measured. RESULTS: It was firstly confirmed that BHB treatments reduced renal biochemical indicators and attenuated glomerular morphological changes of the diabeticrats, with COL IV content decreased in a concentration-dependent manner. Then, BHB treatments were found to up-regulate renal MMP-2 generation of the diabeticrats significantly, while not affecting the increased TGF-β/Smad3 contents. Furthermore, the contents of H3K9bhb in the Mmp-2 promoter were elevated significantly for the middle and high concentrations of BHB treatments, up-regulating MMP-2 generation. CONCLUSION:BHB treatments could up-regulate MMP-2 generation via causing elevated H3K9bhb in its promoter to antagonize glomerulosclerosis in the diabeticrats.
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