WT1 ameliorates podocyte injury via repression of EZH2/β-catenin pathway in diabetic nephropathy

Free Radic Biol Med. 2017 Jul;108:280-299. doi: 10.1016/j.freeradbiomed.2017.03.012. Epub 2017 Mar 16.


Epigenetic modulation of podocyte injury plays a pivotal role in diabetic nephropathy (DN). Wilm's tumor 1 (WT1) has been found to have opposing roles with β-catenin in podocyte biology. Herein, we asked whether the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) promotes WT1-induced podocyte injury via β-catenin activation and the underlying mechanisms. We found that WT1 antagonized EZH2 and ameliorated β-catenin-mediated podocyte injury as demonstrated by attenuated podocyte mesenchymal transition, maintenance of podocyte architectural integrity, decreased podocyte apoptosis and oxidative stress. Further, we provided mechanistical evidence that EZH2 was required in WT1-mediated β-catenin inactivation via repression of secreted frizzled-related protein 1 (SFRP-1), a Wnt antagonist. Moreover, EZH2-mediated silencing of SFRP-1 was due to increased histone 3 lysine 27 trimethylation (H3K27me3) on its promoter region. WT1 favored renal function and decreased podocyte injury in diabetic rats and DN patients. Notably, WT1 exhibited clinical and biological relevance as it was linked to dropped serum creatinine, decreased proteinuria and elevated estimated glomerular filtration rate (eGFR). We propose an epigenetic process via the WT1/EZH2/β-catenin axis in attenuating podocyte injury in DN. Targeting WT1 and EZH2 could be potential therapeutic approaches for DN.

Keywords: Diabetic nephropathy; EZH2; Podocyte injury; WT1; β-catenin.

MeSH terms

  • Animals
  • Apoptosis
  • Creatinine / blood
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition
  • Glomerular Filtration Rate
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Oxidative Stress
  • Podocytes / physiology*
  • Proteinuria
  • Rats
  • WT1 Proteins / metabolism*
  • beta Catenin / metabolism


  • Glycoproteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • WD repeat containing planar cell polarity effector
  • WT1 Proteins
  • beta Catenin
  • Creatinine
  • EZH2 protein, rat
  • Enhancer of Zeste Homolog 2 Protein