Histone deacetylase inhibition attenuates diabetes-associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor

Kidney Int. 2011 Jun;79(12):1312-21. doi: 10.1038/ki.2011.39. Epub 2011 Mar 9.


Clinical trials and experimental studies have highlighted the importance of epigenetic processes in the development of diabetic complications. One of the earliest features of diabetic nephropathy is renal enlargement. The epidermal growth factor (EGF) has a pivotal role in the development of diabetic nephromegaly and transactivation of its receptor has been implicated in the pathogenesis of later-stage disease. As EGF signaling is altered by the acetylation status of histone proteins, we measured the effects of the histone deacetylase (HDAC) inhibitor, vorinostat, in mediating renal enlargement in diabetes focusing on the EGF-EGF receptor (EGFR) axis. In cultured proximal tubule (normal rat kidney) cells, vorinostat treatment reduced EGFR protein and mRNA, and attenuated cellular proliferation. Within 72 h of diabetes induction with streptozotocin, urinary EGF excretion was increased approximately threefold and was unaffected by vorinostat, even though the kidneys of vorinostat-treated diabetic rats had reduced tubular epithelial cell proliferation. Daily treatment of diabetic rats with vorinostat for 4 weeks blunted renal growth and glomerular hypertrophy. Thus, early renal changes in diabetes are amenable to epigenetic intervention. Attenuating effects of HDAC inhibition, although multifactorial, are likely to be mediated in part through downregulation of the EGFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / enzymology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Epigenesis, Genetic / drug effects*
  • ErbB Receptors / drug effects*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Hydroxamic Acids / pharmacology*
  • Hypertrophy
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / enzymology
  • Kidney Glomerulus / pathology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / pathology
  • Male
  • Organ Size / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Vorinostat


  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • RNA, Messenger
  • Vorinostat
  • Egfr protein, rat
  • ErbB Receptors