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Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice
Wenya Weng, Tingwen Ge, Yi Wang, Lulu He, Tinghao Liu, Wanning Wang, Zongyu Zheng, Lechu Yu, Chi Zhang, Xuemian Lu
Diabetes Metab J. 2020;44(4):566-580.   Published online May 15, 2020
DOI: https://doi.org/10.4093/dmj.2019.0089
  • 6,303 View
  • 102 Download
  • 12 Web of Science
  • 11 Crossref
AbstractAbstract PDFPubReader   ePub   
Background

Fibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN.

Methods

Four-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups.

Results

The results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression.

Conclusion

Therefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.

Citations

Citations to this article as recorded by  
  • Fibroblast growth factor 21 alleviates unilateral ureteral obstruction-induced renal fibrosis by inhibiting Wnt/β-catenin signaling pathway
    Wenhui Zhong, Yuheng Jiang, Huizhen Wang, Xiang Luo, Tao Zeng, Huimi Huang, Ling Xiao, Nan Jia, Aiqing Li
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2024; 1871(2): 119620.     CrossRef
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    Anton I. Korbut, Vyacheslav V. Romanov, Vadim V. Klimontov
    Biomedicines.2024; 12(3): 487.     CrossRef
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    David M. Ornitz, Nobuyuki Itoh
    WIREs Mechanisms of Disease.2022;[Epub]     CrossRef
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    Wenxiu Qi, Cheng Hu, Daqing Zhao, Xiangyan Li
    Frontiers in Endocrinology.2022;[Epub]     CrossRef
  • Research Progress of Fibroblast Growth Factor 21 in Fibrotic Diseases
    Min-Qi Jia, Cha-Xiang Guan, Jia-Hao Tao, Yong Zhou, Liang-Jun Yan
    Oxidative Medicine and Cellular Longevity.2022; 2022: 1.     CrossRef
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    Yutong Zou, Lijun Zhao, Junlin Zhang, Yiting Wang, Yucheng Wu, Honghong Ren, Tingli Wang, Yuancheng Zhao, Huan Xu, Lin Li, Nanwei Tong, Fang Liu
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  • The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy
    Junyu Deng, Ye Liu, Yiqiu Liu, Wei Li, Xuqiang Nie
    Journal of Inflammation Research.2021; Volume 14: 5273.     CrossRef
  • Therapeutic effect and mechanism of combined use of FGF21 and insulin on diabetic nephropathy
    Fanrui Meng, Yukai Cao, Mir Hassan Khoso, Kai Kang, Guiping Ren, Wei Xiao, Deshan Li
    Archives of Biochemistry and Biophysics.2021; 713: 109063.     CrossRef
  • FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human
    Emma Henriksson, Birgitte Andersen
    Frontiers in Endocrinology.2020;[Epub]     CrossRef
  • FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases
    Erik J. Tillman, Tim Rolph
    Frontiers in Endocrinology.2020;[Epub]     CrossRef
Basic Research
Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT
Sundong Lin, Lechu Yu, Yongqing Ni, Lulu He, Xiaolu Weng, Xuemian Lu, Chi Zhang
Diabetes Metab J. 2020;44(1):158-172.   Published online October 28, 2019
DOI: https://doi.org/10.4093/dmj.2018.0235
  • 6,050 View
  • 115 Download
  • 38 Web of Science
  • 34 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.

Methods

Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4′-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.

Results

DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).

Conclusion

FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.

Citations

Citations to this article as recorded by  
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    Sudarat Hadpech, Visith Thongboonkerd
    genesis.2024;[Epub]     CrossRef
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