Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy

Kidney Int. 2014 Oct;86(4):712-25. doi: 10.1038/ki.2014.111. Epub 2014 Apr 9.

Abstract

Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-β (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / complications
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology*
  • Enzyme Inhibitors / pharmacology
  • Gene Silencing
  • Glucose / pharmacology
  • Glycation End Products, Advanced / pharmacology
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylases / analysis
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Male
  • Mice
  • Podocytes / chemistry
  • Podocytes / metabolism*
  • Podocytes / pathology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Repressor Proteins / analysis
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / pharmacology
  • Up-Regulation

Substances

  • Enzyme Inhibitors
  • Glycation End Products, Advanced
  • RNA, Messenger
  • Repressor Proteins
  • STAT1 Transcription Factor
  • Stat1 protein, rat
  • Transforming Growth Factor beta
  • HDAC2 protein, human
  • HDAC4 protein, human
  • HDAC4 protein, rat
  • Hdac2 protein, mouse
  • Hdac2 protein, rat
  • Hdac5 protein, mouse
  • Hdac5 protein, rat
  • Histone Deacetylase 2
  • Histone Deacetylases
  • Glucose