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Berberine Improves the Protective Effects of Metformin on Diabetic Nephropathy in db/db Mice through Trib1-dependent Inhibiting Inflammation

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Abstract

Purpose

Diabetic nephropathy (DN), one of severe diabetic complications in the diabetes, is the main cause of end stage renal disease (ESRD). Notably, the currently available medications used to treat DN remain limited. Here, we determined whether berberine (BBR) could enhance the anti-diabetic nephropathy activities of metformin (Met) and explored its possible mechanisms.

Method

The anti-diabetic nephropathy properties were systematically analyzed in the diabetic db/db mice treated with Met, BBR or with combination of Met and BBR.

Results

We found that both single Met and BBR treatments, and combination therapy could lower blood glucose, and ameliorate insulin resistance. The improvement of lipids metabolism by co-administration was more evident, as indicated by reduced serum cholesterol and less fat accumulation in the liver. Further, it was found that Met and BBR treatments, and co-administration could attenuate the progression of DN. However, anti-diabetic nephropathy activities of Met were enhanced when combined with BBR, as evidenced by improved renal function and histological abnormalities of diabetic kidney. Mechanistically, BBR enhanced renal-protective effects of Met primarily through potently promoting expression of Trib1, which subsequently downregulated the increased protein levels of CCAAT/enhancer binding protein α (C/EBPα), and eventually inhibited fatty synthesis proteins and nuclear factor kappa-B (NF-κB) signaling.

Conclusion

Our data provide novel insight that co-administration of BBR and Met exerts a preferable activity of anti-diabetic nephropathy via collectively enhancing lipolysis and inhibiting inflammation. Combination therapy with these two drugs may provide an effective therapeutic strategy for the medical treatment of diabetic nephropathy.

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Funding

This work was supported by a grant from Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (No.2019-I2M-1–005, 2020-I2M-2–011).

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Authors and Affiliations

  1. Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100193, China

    Bin Zhang, Xuelian Zhang, Chenyang Zhang, Guibo Sun & Xiaobo Sun

  2. Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China

    Bin Zhang, Xuelian Zhang, Chenyang Zhang, Guibo Sun & Xiaobo Sun

  3. Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, 100193, China

    Bin Zhang, Xuelian Zhang, Chenyang Zhang, Guibo Sun & Xiaobo Sun

  4. Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, 100193, China

    Bin Zhang, Xuelian Zhang, Chenyang Zhang, Guibo Sun & Xiaobo Sun

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  1. Bin Zhang
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  2. Xuelian Zhang
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Contributions

GS and XS designed and supervised the whole project. BZ, XZ, CZ, and NL conducted the experiments and BZ processed the data, BZ wrote the paper and ZD helped to revised it. All authors read and approved the final manuscript.

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Correspondence to Guibo Sun or Xiaobo Sun.

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Zhang, B., Zhang, X., Zhang, C. et al. Berberine Improves the Protective Effects of Metformin on Diabetic Nephropathy in db/db Mice through Trib1-dependent Inhibiting Inflammation. Pharm Res 38, 1807–1820 (2021). https://doi.org/10.1007/s11095-021-03104-x

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