title: Heat shock protein 90 inhibition abrogates TLR4-mediated NF-κB activity and reduces renal ischemia-reperfusion injury.
abstract: Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury. Toll-like receptor 4 (TLR4) mediates sterile inflammation following renal IRI. Heat shock protein 90 (Hsp90) inhibition is a potential strategy to reduce IRI, and AT13387 is a novel Hsp90 inhibitor with low toxicity. This study assessed if pre-treatment with AT13387 could reduce renal IRI and established if the mechanism of protection involved a reduction in inflammatory signalling. Mice were pre-treated with AT13387 prior to renal IRI. 24 h later, renal function was determined by serum creatinine, kidney damage by tubular necrosis score, renal TLR4 expression by PCR and inflammation by cytokine array. In vitro, human embryonic kidney cells were co-transfected to express TLR4 and a secreted alkaline phosphatase NF-κB reporter. Cells were pre-treated with AT13387 and exposed to endotoxin-free hyaluronan to stimulate sterile TLR4-specific NF-κB inflammatory activation. Following renal IRI, AT13387 significantly reduced serum creatinine, tubular necrosis, TLR4 expression and NF-κB-dependent chemokines. In vitro, AT13387-treatment resulted in breakdown of IκB kinase, which abolished TLR4-mediated NF-κB activation by hyaluronan. AT13387 is a new agent with translational potential that reduces renal IRI. The mechanism of protection may involve breakdown of IκB kinase and repression of TLR4-mediated NF-κB inflammatory activity.
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Neill
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Duncan
authors.initials: D
authors.lastname: Humphries
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: George
authors.initials: G
authors.lastname: Tse
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Lorna P
authors.initials: LP
authors.lastname: Marson
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dhaliwal
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SA.
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wigmore
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4SA.
authors.forename: Ewen M
authors.initials: EM
authors.lastname: Harrison
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D054833:Isoindoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051550:I-kappa B Kinase; D000469:Alkaline Phosphatase; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone