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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.

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  • Additional Information
    • Source:
      Publisher: Korean Diabetes Association Country of Publication: Korea (South) NLM ID: 101556588 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2233-6087 (Electronic) Linking ISSN: 22336079 NLM ISO Abbreviation: Diabetes Metab J Subsets: MEDLINE
    • Publication Information:
      Original Publication: Seoul : Korean Diabetes Association
    • Subject Terms:
      Epithelial-Mesenchymal Transition*; Diabetes Mellitus, Experimental/*pathology ; Diabetic Nephropathies/*pathology ; Fibroblast Growth Factors/*metabolism ; Kidney Tubules/*pathology ; Proto-Oncogene Proteins c-akt/*metabolism; Animals ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Type 1/complications ; Diabetic Nephropathies/metabolism ; Fibrosis ; Kidney Tubules/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Signal Transduction ; Smad2 Protein/metabolism ; Streptozocin ; Transforming Growth Factor beta/metabolism ; Tumor Suppressor Protein p53/metabolism
    • Abstract:
      Competing Interests: No potential conflict of interest relevant to this article was reported.
      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.
      (Copyright © 2020 Korean Diabetes Association.)
    • References:
      J Clin Endocrinol Metab. 2015 Apr;100(4):1368-75. (PMID: 25625802)
      PLoS One. 2013 Dec 09;8(12):e82287. (PMID: 24349248)
      Mol Cancer Res. 2003 Dec;1(14):1001-8. (PMID: 14707283)
      Cell. 2009 Nov 25;139(5):871-90. (PMID: 19945376)
      Trends Biochem Sci. 2002 Sep;27(9):462-7. (PMID: 12217521)
      Endocrinology. 2015 Mar;156(3):1156-70. (PMID: 25560828)
      J Clin Med. 2015 Dec 30;5(1):. (PMID: 26729181)
      Cytokine Growth Factor Rev. 2011 Jun;22(3):131-9. (PMID: 21757394)
      Chin Med J (Engl). 2018 Mar 5;131(5):532-538. (PMID: 29483386)
      PLoS One. 2014 Mar 20;9(3):e92574. (PMID: 24651118)
      Diabetologia. 2018 Feb;61(2):482-495. (PMID: 29085990)
      J Pharmacol Sci. 2018 Apr;136(4):218-227. (PMID: 29551286)
      Diabetes. 2017 Oct;66(10):2691-2703. (PMID: 28747378)
      J Renal Inj Prev. 2016 Apr 24;5(2):79-84. (PMID: 27471739)
      PLoS One. 2012;7(12):e49257. (PMID: 23251339)
      Endocrinology. 2013 Sep;154(9):3366-76. (PMID: 23825123)
      J Clin Invest. 2009 Jun;119(6):1420-8. (PMID: 19487818)
      Aging Cell. 2017 Apr;16(2):387-400. (PMID: 28127848)
      FASEB J. 2017 Jan;31(1):308-319. (PMID: 27881486)
      Transplant Proc. 2017 Oct;49(8):1791-1796. (PMID: 28923627)
      Cell Death Dis. 2018 Feb 14;9(2):227. (PMID: 29445083)
      Diabetes. 2011 Jan;60(1):280-7. (PMID: 20952520)
      Eur J Cancer. 2014 Apr;50(6):1184-94. (PMID: 24447832)
      Mol Cell Biol. 2007 Dec;27(23):8228-42. (PMID: 17875924)
      J Cell Mol Med. 2014 May;18(5):895-906. (PMID: 24597671)
      Am J Transl Res. 2017 Oct 15;9(10):4492-4501. (PMID: 29118911)
      J Mol Cell Cardiol. 2014 Dec;77:42-52. (PMID: 25268649)
      J Diabetes Complications. 2018 Aug;32(8):729-736. (PMID: 29907326)
      Cell Signal. 2018 Mar;43:1-10. (PMID: 29191563)
      Expert Rev Mol Med. 2010 May 27;12:e17. (PMID: 20504380)
      Metabolism. 2010 Nov;59(11):1656-62. (PMID: 20423749)
      Exp Cell Res. 2016 Aug 15;346(2):147-56. (PMID: 27364911)
      Clin Endocrinol (Oxf). 2014 Jun;80(6):918-24. (PMID: 24612017)
      Diabetes. 2006 Sep;55(9):2470-8. (PMID: 16936195)
      J Biol Chem. 2005 Nov 18;280(46):38795-802. (PMID: 16159876)
      Am J Cancer Res. 2015 Apr 15;5(5):1762-74. (PMID: 26175944)
      PLoS One. 2013 Dec 09;8(12):e82275. (PMID: 24349242)
      J Clin Invest. 2014 Jun;124(6):2333-40. (PMID: 24892707)
      Sci Rep. 2016 Oct 19;6:35483. (PMID: 27759037)
      Ren Fail. 2017 Nov;39(1):474-483. (PMID: 28413908)
      Int J Mol Med. 2018 May;41(5):2704-2714. (PMID: 29436579)
      Ir J Med Sci. 2017 Aug;186(3):785-794. (PMID: 28181108)
      Cell. 2008 May 30;133(5):767-9. (PMID: 18510920)
      Diabetes Obes Metab. 2016 Jul;18(7):641-7. (PMID: 26743887)
      Mol Endocrinol. 2015 Oct;29(10):1400-13. (PMID: 26308386)
      PLoS One. 2017 Jun 5;12(6):e0178971. (PMID: 28582462)
      J Clin Invest. 2009 Jun;119(6):1417-9. (PMID: 19487817)
      FASEB J. 2018 Jun;32(6):3423-3433. (PMID: 29401620)
      Clin Chim Acta. 2019 Feb;489:196-202. (PMID: 29108880)
      Am J Physiol Endocrinol Metab. 2015 Jul 1;309(1):E45-54. (PMID: 25968574)
    • Grant Information:
      2015KYB236 International Medical and Healthy Technological Grant of Zhejiang Province; 2018KY769 International Medical and Healthy Technological Grant of Zhejiang Province; 81670767 International NSFC; 81700732 International NSFC
    • Contributed Indexing:
      Keywords: Epithelial-mesenchymal transition; Fibroblast growth factor 21; Fibrosis; Kidney; Transforming growth factor beta; Tumor suppressor protein p53
    • Accession Number:
      0 (Smad2 Protein)
      0 (Transforming Growth Factor beta)
      0 (Tumor Suppressor Protein p53)
      0 (fibroblast growth factor 21)
      5W494URQ81 (Streptozocin)
      62031-54-3 (Fibroblast Growth Factors)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
    • Publication Date:
      Date Created: 20191109 Date Completed: 20210615 Latest Revision: 20210615
    • Publication Date:
      20250114
    • Accession Number:
      PMC7043973
    • Accession Number:
      10.4093/dmj.2018.0235
    • Accession Number:
      31701691