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Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat

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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.

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81600384 and 81470595) and the Hebei Natural Science Foundation (H2015206101).

Funding

This study was supported by grants from the National Natural Science Foundation of China (81600384 and 81470595) and the Hebei Natural Science Foundation (H2015206101).

Author information

Author notes

  1. Weigang Luo, Yijin Yu and Hao Wang contributed equally.

Authors and Affiliations

  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

    Weigang Luo, Yijin Yu, Yu Wang, Minling Huang, Chenhao Xuan & Yanning Li

  2. Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China

    Hao Wang, Kun Liu & Jinsheng Qi

  3. 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

    Jinsheng Qi

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  1. Weigang Luo
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Contributions

WL, YY, HW, MH and CX conducted the experiments. KL and YW analyzed the data. WL and YL wrote the manuscript. YL and JQ convinced the whole project and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yanning Li or Jinsheng Qi.

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Conflicts of interest

The authors declare that there is no conflict of interest.

Ethical approval

Ethics Review Committee for Animal Experimentation of Hebei Medical University.

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A verbal informed consent was obtained from each study subject for publication.

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This article belongs to the topical collection diabetic nephropathy, managed by Giuseppe Pugliese.

Electronic supplementary material

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592_2020_1552_MOESM1_ESM.tif

Effects of β-hydroxybutyrate (BHB) on the binding of NF-κB to the Mmp-2 promoter. a The protein content of NF-κB p65 was detected and calculated. b After DNA pull-down, the protein contents of NF-κB p65 were detected. c The ratios of pull-down NF-κB p65 to its input (nuclear NF-κB p65) were calculated to show the relative bound contents. **p < 0.01 or *p < 0.05, vs control (Con) group (n = 3). DM, diabetes mellitus; BHB1, DM + low concentration BHB; BHB2, DM + middle concentration BHB; BHB3, DM + high concentration BHB (TIF 702 kb)

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Luo, W., Yu, Y., Wang, H. et al. Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat. Acta Diabetol 57, 1501–1509 (2020). https://doi.org/10.1007/s00592-020-01552-2

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  • DOI: https://doi.org/10.1007/s00592-020-01552-2

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