title: LPS-induced delayed preconditioning is mediated by Hsp90 and involves the heat shock response in mouse kidney.
abstract: BACKGROUND
  We and others demonstrated previously that preconditioning with endotoxin (LPS) protected from a subsequent lethal LPS challenge or from renal ischemia-reperfusion injury (IRI). LPS is effective in evoking the heat shock response, an ancient and essential cellular defense mechanism, which plays a role in resistance to, and recovery from diseases. Here, by using the pharmacological Hsp90 inhibitor novobiocin (NB), we investigated the role of Hsp90 and the heat shock response in LPS-induced delayed renal preconditioning.
  
  
  METHODS
  Male C57BL/6 mice were treated with preconditioning (P: 2 mg/kg, i.p.) and subsequent lethal (L: 10 mg/kg, i.p.) doses of LPS alone or in combination with NB (100 mg/kg, i.p.). Controls received saline (C) or NB.
  
  
  RESULTS
  Preconditioning LPS conferred protection from a subsequent lethal LPS treatment. Importantly, the protective effect of LPS preconditioning was completely abolished by a concomitant treatment with NB. LPS induced a marked heat shock protein increase as demonstrated by Western blots of Hsp70 and Hsp90. NB alone also stimulated Hsp70 and Hsp90 mRNA but not protein expression. However, Hsp70 and Hsp90 protein induction in LPS-treated mice was abolished by a concomitant NB treatment, demonstrating a NB-induced impairment of the heat shock response to LPS preconditioning.
  
  
  CONCLUSIONS
  LPS-induced heat shock protein induction and tolerance to a subsequent lethal LPS treatment was prevented by the Hsp90 inhibitor, novobiocin. Our findings demonstrate a critical role of Hsp90 in LPS signaling, and a potential involvement of the heat shock response in LPS-induced preconditioning.
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kaucsár
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Bodor
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Godó
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szalay
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Révész
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Zalán
authors.initials: Z
authors.lastname: Németh
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Mózes
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; Hungarian Academy of Sciences-Semmelweis University, Nephrology Research Group, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Rosivall
authors.affiliation: Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Sőti
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Hamar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects*; D019194:Ischemic Preconditioning; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009675:Novobiocin / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014508:Urea / Q000097:blood
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008070:Lipopolysaccharides; D020011:Protective Agents; D012333:RNA, Messenger; D009675:Novobiocin; D014508:Urea