title: Epigenetic modifiers exert renal toxicity through induction of p66shc.
abstract: OBJECTIVE
  Trichostatin A (TSA) and 5-azacytidine (5AZA) induce reactive oxygen species (ROS)-mediated injury in renal proximal tubule cells. Since TSA and 5AZA are activators of p66shc, we questioned whether p66shc may mediate renal toxicity of TSA- and 5AZA.
  
  
  METHODS
  Renal proximal tubule cells were treated with either TSA or 5AZA for 24 hours followed by treatment with 200 μM H(2)O(2). Expression of p66shc and activity of its promoter, as well as its mitochondrial and cytochrome c binding were determined. Impact of knockdown of p66shc and mutation of its cytochrome c-binding site on ROS production and cell injury was studied.
  
  
  RESULTS
  TSA, and 5AZA increased expression of p66shc through induction of its promoter and also increased its mitochondrial/cytochrome c binding. Knockdown or mutation of the cytochrome c binding site of p66shc attenuated ROS production and cell injury.
  
  
  CONCLUSIONS
  Therapeutic means that interfere with induction of p66shc may ameliorate renal toxicity of those epigenetic modifiers.
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A. iarany@umc.edu
authors.forename: Istvan
authors.initials: I
authors.lastname: Arany
authors.forename: Jeb S
authors.initials: JS
authors.lastname: Clark
authors.forename: Istvan
authors.initials: I
authors.lastname: Ember
authors.forename: Luis A
authors.initials: LA
authors.lastname: Juncos
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D001665:Binding Sites; D002461:Cell Line, Transformed; D045304:Cytochromes c / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C012589:trichostatin A; D045304:Cytochromes c; D001374:Azacitidine