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Astragalin ameliorates renal injury in diabetic mice by modulating mitochondrial quality control via AMPK-dependent PGC1α pathway

Acta Pharmacologica Sinica volume 44, pages 1676–1686 (2023)Cite this article

Abstract

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus, and oxidative stress and mitochondrial dysfunction play an important role in this process. It has been shown that aldose reductase (ALR2) catalyzes NADPH-dependent reduction of glucose to sorbitol, resulting in oxidative stress and mitochondrial dysfunction in diabetic patients. Astragalin (AG), a flavonoid extracted from Thesium chinense Turcz., shows an inhibitory activity on ALR2. In this study, we investigated the therapeutic effects of AG against renal injury in streptozocin (STZ)-induced diabetic mouse model. Diabetic mice were orally administered AG (5, 10 mg·kg−1·d−1) for 4 weeks. We showed that AG treatment greatly improved the proteinuria and ameliorated renal pathological damage without affecting the elevated blood glucose in diabetic mice. Furthermore, AG treatment significantly suppressed highly activated ALR2, and reduced oxidative stress in the kidney of diabetic mice and in high glucose and lipids-stimulated HK2 cells in vitro. We demonstrated that AG treatment modulated mitochondrial quality control and ameliorated apoptosis, boosting mitochondrial biogenesis, maintaining mitochondrial dynamic homeostasis, and improving energy metabolism disorder in vivo and in vitro. In high glucose and lipids-stimulated HK2 cells, we found that AG (20 μM) restored the phosphorylation level of AMPK, and upregulated the expression and transcriptional activity of PGC1α, whereas treatment with H2O2, blockade of AMPK with Compound C or knockdown of AMPKα with siRNA abolished the protective effect of AG on mitochondrial function, suggesting that antioxidant effects and activation of AMPK-dependent PGC1α pathway might be the molecular mechanisms underlying the protective effects of AG on mitochondrial quality control. We conclude that AG could be a promising drug candidate for the treatment of diabetic renal injury through activating AMPK.

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Fig. 1: Astragalin (AG) improves renal function in STZ-induced diabetic mice.
Fig. 2: Astragalin (AG) ameliorates renal pathological damage in STZ-induced diabetic mice.
Fig. 3: Astragalin (AG) inhibits aldose reductase activity and ameliorates oxidative stress in the kidney of STZ-induced diabetic mice.
Fig. 4: Astragalin (AG) alleviates mitochondrial dysfunction in the kidney of STZ-induced diabetic mice.
Fig. 5: Astragalin (AG) facilitates AMPK/PGC1α activation pathway and inhibits mitochondria-dependent apoptosis in the kidney of STZ-induced diabetic mice.
Fig. 6: Astragalin (AG) modulates mitochondrial quality control via antioxidant effect and AMPK activation in the HK2 cells.
Fig. 7: Astragalin (AG) upregulated AMPK-mediated PGC1α expression contributing to the restoration of mitochondrial biogenesis and suppression of apoptosis.

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References

  1. Chinese Diabetes Society. Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition). Int J Endocrinol Metab. 2021;41:482–548.

    Google Scholar 

  2. Forbes JM, Thorburn DR. Mitochondrial dysfunction in diabetic kidney disease. Nat Rev Nephrol. 2018;14:291–312.

    Article  CAS  PubMed  Google Scholar 

  3. Bhargava P, Schnellmann RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol. 2017;13:629–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qin X, Jiang M, Zhao Y, Gong J, Su H, Yuan F, et al. Berberine protects against diabetic kidney disease via promoting PGC-1α-regulated mitochondrial energy homeostasis. Br J Pharmacol. 2020;177:3646–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Qin X, Zhao Y, Gong J, Huang W, Su H, Yuan F, et al. Berberine protects glomerular podocytes via inhibiting Drp1-mediated mitochondrial fission and dysfunction. Theranostics. 2019;9:1698–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yuan Y, Yuan L, Li L, Liu F, Liu J, Chen Y, et al. Mitochondrial transfer from mesenchymal stem cells to macrophages restricts inflammation and alleviates kidney injury in diabetic nephropathy mice via PGC-1α activation. Stem Cells. 2021;39:913–28.

    Article  CAS  PubMed  Google Scholar 

  7. Terubayashi H, Sato S, Nishimura C, Kador PF, Kinoshita JH. Localization of aldose and aldehyde reductase in the kidney. Kidney Int. 1989;36:843–51.

    Article  CAS  PubMed  Google Scholar 

  8. Tang WH, Stitham J, Jin Y, Liu R, Lee SH, Du J, et al. Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation. 2014;129:1598–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. He J, Gao HX, Yang N, Zhu XD, Sun RB, Xie Y, et al. The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation. Acta Pharmacol Sin. 2019;40:86–97.

    Article  CAS  PubMed  Google Scholar 

  10. Peng L, Gao X, Nie L, Xie J, Dai T, Shi C, et al. Astragalin attenuates dextran sulfate sodium (DSS)-induced acute experimental colitis by alleviating gut microbiota dysbiosis and inhibiting NF-κB activation in mice. Front Immunol. 2020;11:2058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim YH, Kang MK, Lee EJ, Kim DY, Oh H, Kim SI, et al. Astragalin inhibits cigarette smoke-induced pulmonary thrombosis and alveolar inflammation and disrupts par activation and oxidative stress-responsive MAPK-signaling. Int J Mol Sci. 2021;22:3692.

  12. Choung WJ, Hwang SH, Ko DS, Kim SB, Kim SH, Jeon SH, et al. Enzymatic synthesis of a novel kaempferol-3-o-β-d-glucopyranosyl-(1→4)-o-α-d-glucopyranoside using cyclodextrin glucanotransferase and its inhibitory effects on aldose reductase, inflammation, and oxidative stress. J Agric Food Chem. 2017;65:2760–7.

    Article  CAS  PubMed  Google Scholar 

  13. Liu CH, Chen HL, Zha XL, Zhu XX. Isolation and purification of aldose reductase and analysis of its properties. Acta Acad Med Shanghai. 1996;6:427–30.

  14. Ighodaro OM. Molecular pathways associated with oxidative stress in diabetes mellitus. Biomed Pharmacother. 2018;108:656–62.

    Article  CAS  PubMed  Google Scholar 

  15. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19:121–35.

    Article  CAS  PubMed  Google Scholar 

  16. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78–90.

    Article  CAS  PubMed  Google Scholar 

  17. Ricciardi CA, Gnudi L. Kidney disease in diabetes: from mechanisms to clinical presentation and treatment strategies. Metab Clin Exp. 2021;124:154890.

  18. Schapira AH. Mitochondrial diseases. Lancet. 2012;379:1825–34.

    Article  CAS  PubMed  Google Scholar 

  19. Kou G, Li Z, Wu C, Liu Y, Hu Y, Guo L, et al. Citrus tangeretin improves skeletal muscle mitochondrial biogenesis via activating the AMPK-PGC1-α pathway in vitro and in vivo: a possible mechanism for its beneficial effect on physical performance. J Agric Food Chem. 2018;66:11917–25.

    Article  CAS  PubMed  Google Scholar 

  20. Kador PF, Wyman M, Oates PJ. Aldose reductase, ocular diabetic complications and the development of topical Kinostat®. Prog Retin Eye Res. 2016;54:1–29.

    Article  CAS  PubMed  Google Scholar 

  21. Tang WH, Martin KA, Hwa J. Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol. 2012;3:87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kowalczyk P, Sulejczak D, Kleczkowska P, Bukowska OI, Kucia M, Popiel M, et al. Mitochondrial oxidative stress-a causative factor and therapeutic target in many diseases. Int J Mol Sci. 2021;22:13384.

  23. Wang J, Zhu P, Li R, Ren J, Zhang Y, Zhou H. Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2. Theranostics. 2020;10:384–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tirichen H, Yaigoub H, Xu W, Wu C, Li R, Li Y. Mitochondrial reactive oxygen species and their contribution in chronic kidney disease progression through oxidative stress. Front Physiol. 2021;12:627837.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85–100.

    Article  CAS  PubMed  Google Scholar 

  26. Wu SB, Wu YT, Wu TP, Wei YH. Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress. Biochim Biophys Acta. 2014;1840:1331–44.

    Article  CAS  PubMed  Google Scholar 

  27. Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, et al. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD+ elevation. Aging Cell. 2016;15:416–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Haemmerle G, Moustafa T, Woelkart G, Büttner S, Schmidt A, van de Weijer T, et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nat Med. 2011;17:1076–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li SY, Susztak K. The role of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in kidney disease. Semin Nephrol. 2018;38:121–6.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dong YZ, Li L, Espe M, Lu KL, Rahimnejad S. Hydroxytyrosol attenuates hepatic fat accumulation via activating mitochondrial biogenesis and autophagy through the AMPK pathway. J Agric Food Chem. 2020;68:9377–86.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number 82073859 and 81673658).

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Authors and Affiliations

  1. School of Pharmacy, Fudan University, Shanghai, 201203, China

    Meng-yao Sun, Hui-jing Ye, Chen Zheng, Zi-jie Jin, Yan Yuan & Hong-bo Weng

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  1. Meng-yao Sun
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Contributions

MYS and HBW conceptualized the study. MYS and HJY contributed to the animal experiments. MYS and CZ contributed to the molecular biology experiments. MYS and ZJ contributed to the data collection and statistical analysis. YY contributed to the methodology. MYS and HBW drafted and finalized the paper.

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Correspondence to Hong-bo Weng.

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Sun, My., Ye, Hj., Zheng, C. et al. Astragalin ameliorates renal injury in diabetic mice by modulating mitochondrial quality control via AMPK-dependent PGC1α pathway. Acta Pharmacol Sin 44, 1676–1686 (2023). https://doi.org/10.1038/s41401-023-01064-z

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