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PLoS One. 2014 Mar 19;9(3):e92004. doi: 10.1371/journal.pone.0092004. eCollection 2014.

LPS-induced delayed preconditioning is mediated by Hsp90 and involves the heat shock response in mouse kidney.

Author information

1
Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
2
Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; Hungarian Academy of Sciences-Semmelweis University, Nephrology Research Group, Budapest, Hungary.
3
Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.

Abstract

INTRODUCTION:

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.

CONCLUSION:

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.

PMID:
24646925
PMCID:
PMC3960147
DOI:
10.1371/journal.pone.0092004
[Indexed for MEDLINE]
Free PMC Article
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