Item request has been placed! ×
Item request cannot be made. ×
loading  Processing Request

Advanced Glycation End Products Mediate Epigenetic Alteration of H3K27me3 in Renal Proximal Tubular Cells: Potential Role in Metabolic Memory.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI
    • Subject Terms:
      Glycation End Products, Advanced*/metabolism ; Kidney Tubules, Proximal*/metabolism ; Kidney Tubules, Proximal*/pathology ; Kidney Tubules, Proximal*/cytology ; Histones*/metabolism ; Epigenesis, Genetic*; Enhancer of Zeste Homolog 2 Protein/metabolism ; Enhancer of Zeste Homolog 2 Protein/genetics ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Animals ; Mice ; Male ; Mice, Inbred C57BL ; Methylation ; Humans
    • Abstract:
      The accumulation of advanced glycation end products (AGEs) is a hallmark of prolonged high glucose levels in diabetes mellitus. We have previously reported that hypoxia and AGEs cause epigenetic modification of the repressive mark H3K27me3 in podocytes by downregulation of enhancer of zeste homolog 2 (EZH2) and nuclear inhibitor of protein phosphatase 1 (NIPP1). However, their impact on proximal tubular cells remains unclear. The aim of this study was to investigate the role of AGEs and diabetes on the epigenetic modifications of EZH2 and H3K27me3 in proximal tubular cells and in diabetic (db/db) mice. Our results show that AGEs reduced EZH2 expression in TKPTS cells, thereby decreasing the tri-methylation of H3K27. qRT-PCR analysis revealed upregulation of genes known to contribute to diabetic nephropathy and kidney injury as Ctgf, Snai1, and p27Kip1. Consistently, immunofluorescent staining of renal sections from db/db mice confirmed the reduction in H3K27me3 levels in proximal tubules compared to non-diabetic controls. In summary, we show that AGEs induce epigenetic changes in proximal tubular cells by suppressing EZH2, thereby facilitating the transcription of genes involved in progression of diabetic nephropathy. These results provide new insights into metabolic memory, a process in which prior poor glucose control triggers ongoing renal damage despite current normoglycemia.
    • References:
      J Am Soc Nephrol. 2016 Jul;27(7):2021-34. (PMID: 26534922)
      Int J Mol Sci. 2020 Jan 31;21(3):. (PMID: 32023873)
      Cell. 1996 Feb 9;84(3):491-5. (PMID: 8608603)
      Curr Opin Genet Dev. 2004 Apr;14(2):155-64. (PMID: 15196462)
      Cells. 2022 Feb 17;11(4):. (PMID: 35203361)
      Diabetologia. 2015 Mar;58(3):443-55. (PMID: 25481708)
      Nat Rev Nephrol. 2010 Jun;6(6):352-60. (PMID: 20421886)
      Arthritis Res Ther. 2009;11(5):R136. (PMID: 19735566)
      Methods Enzymol. 1985;113:400-19. (PMID: 2868390)
      J Biol Chem. 2018 Sep 7;293(36):13805-13814. (PMID: 28912274)
      Am J Nephrol. 2020;51(9):676-692. (PMID: 32854097)
      Cell Div. 2020 May 25;15:8. (PMID: 32508971)
      Am J Physiol Renal Physiol. 2003 Mar;284(3):F488-97. (PMID: 12419774)
      Am J Pathol. 2003 Apr;162(4):1123-37. (PMID: 12651605)
      Biomedicines. 2023 Sep 07;11(9):. (PMID: 37760919)
      Front Physiol. 2023 Mar 29;14:1154551. (PMID: 37064891)
      Ren Fail. 1998 Mar;20(2):319-24. (PMID: 9574458)
      Cell Death Dis. 2019 May 1;10(5):355. (PMID: 31043583)
      Science. 2007 Oct 19;318(5849):447-50. (PMID: 17761849)
      Signal Transduct Target Ther. 2024 Feb 28;9(1):38. (PMID: 38413567)
      Glomerular Dis. 2024 Nov 13;4(1):211-226. (PMID: 39649441)
      Am J Physiol Renal Physiol. 2003 Jun;284(6):F1138-44. (PMID: 12736165)
      Cell Death Dis. 2021 Jan 5;12(1):44. (PMID: 33414422)
      Oxid Med Cell Longev. 2020 Mar 18;2020:3818196. (PMID: 32256950)
      Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):664-74. (PMID: 25614281)
      Genes Dev. 2006 May 1;20(9):1123-36. (PMID: 16618801)
      Kidney Int. 2005 Oct;68(4):1583-9. (PMID: 16164635)
      J Med Chem. 2024 Oct 24;67(20):17964-17979. (PMID: 39392180)
      Genes Dev. 2002 Nov 15;16(22):2893-905. (PMID: 12435631)
      PLoS One. 2023 Feb 24;18(2):e0279655. (PMID: 36827456)
      Nephrol Dial Transplant. 2017 Dec 01;32(12):2017-2034. (PMID: 28992060)
      Nature. 1961 Apr 22;190:372-3. (PMID: 13764598)
      Genes Dev. 2007 May 1;21(9):1050-63. (PMID: 17437993)
      Kidney Int. 2009 Mar;75(6):605-16. (PMID: 19037249)
      Nature. 2001 Dec 13;414(6865):813-20. (PMID: 11742414)
      Cells. 2020 Oct 03;9(10):. (PMID: 33023010)
      Sci Rep. 2017 Dec 4;7(1):16878. (PMID: 29203879)
      J Biol Chem. 2019 Aug 23;294(34):12695-12707. (PMID: 31266808)
      Cells. 2021 Sep 26;10(10):. (PMID: 34685528)
      Nutr Metab Cardiovasc Dis. 2013 Oct;23(10):913-9. (PMID: 23786818)
      Kidney Int. 2007 Nov;72(9):1113-21. (PMID: 17728703)
      FASEB J. 2025 May 15;39(9):e70605. (PMID: 40326780)
      Kidney Int. 2014 Jul;86(1):103-17. (PMID: 24476693)
      Mol Cell. 2004 Jul 2;15(1):57-67. (PMID: 15225548)
      Clin Chem. 1986 Oct;32(10 Suppl):B37-41. (PMID: 3530538)
      Cell. 2007 May 18;129(4):823-37. (PMID: 17512414)
      Curr Opin Genet Dev. 2017 Apr;43:31-37. (PMID: 27940208)
      J Neurosci. 2008 Apr 23;28(17):4521-7. (PMID: 18434530)
      Cardiovasc Diabetol. 2024 Apr 5;23(1):122. (PMID: 38580969)
      J Biol Chem. 2014 Oct 17;289(42):29001-13. (PMID: 25204661)
      Brain Res. 2006 Dec 18;1126(1):50-5. (PMID: 16962077)
      J Mol Med (Berl). 2001 Jul;79(7):382-9. (PMID: 11466560)
      Free Radic Biol Med. 2017 Jul;108:280-299. (PMID: 28315733)
      World J Diabetes. 2023 Mar 15;14(3):209-221. (PMID: 37035229)
      Nat Commun. 2021 Jan 29;12(1):719. (PMID: 33514712)
      Acta Pharmacol Sin. 2014 Feb;35(2):161-74. (PMID: 24362326)
      Acta Diabetol. 2011 Mar;48(1):61-9. (PMID: 20857148)
      Diabetes Care. 2021 Sep 21;:. (PMID: 34548284)
      PLoS One. 2013 Aug 12;8(8):e70441. (PMID: 23950936)
      Methods. 2001 Dec;25(4):402-8. (PMID: 11846609)
      Am J Pathol. 2001 Mar;158(3):1091-100. (PMID: 11238057)
      Ageing Res Rev. 2014 May;15:146-60. (PMID: 24742501)
      J Clin Invest. 2001 Dec;108(12):1853-63. (PMID: 11748269)
      Nat Rev Nephrol. 2019 Jun;15(6):327-345. (PMID: 30894700)
      Diabetes. 2010 Jan;59(1):249-55. (PMID: 19833897)
      J Exp Clin Cancer Res. 2014 Aug 02;33:62. (PMID: 25084828)
      Am J Physiol Renal Physiol. 2023 Jul 1;325(1):F121-F133. (PMID: 37167274)
      Kidney Int. 2018 Apr;93(4):803-813. (PMID: 29477239)
      J Clin Lab Anal. 2022 Apr;36(4):e24280. (PMID: 35257412)
      J Clin Med. 2023 Apr 12;12(8):. (PMID: 37109170)
      Genes Dev. 2004 Jul 1;18(13):1592-605. (PMID: 15231737)
      Front Med (Lausanne). 2022 Aug 09;9:970423. (PMID: 36017003)
      J Ethnopharmacol. 2023 Sep 15;313:116601. (PMID: 37146843)
      Diabetes. 2005 Jun;54(6):1615-25. (PMID: 15919781)
    • Contributed Indexing:
      Keywords: 3-deazaneplanocin A; AGEs; DZNep; EZH2; H3K27me3; advanced glycated end products; db/db mice; enhancer of zeste homolog 2; histone 3 K27 tri-methylation; metabolic memory
    • Accession Number:
      0 (Glycation End Products, Advanced)
      0 (Histones)
      EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
      EC 2.1.1.43 (Ezh2 protein, mouse)
    • Publication Date:
      Date Created: 20251113 Date Completed: 20251113 Latest Revision: 20251116
    • Publication Date:
      20260130
    • Accession Number:
      PMC12607550
    • Accession Number:
      10.3390/cells14211729
    • Accession Number:
      41227374