Heat shock protein 90 inhibition abrogates TLR4-mediated NF-kB activity and reduces renal ischemia-reperfusion injury

Stephen O'Neill*, Duncan Humphries, George Tse, Lorna P. Marson, Kevin Dhaliwal, Jeremy Hughes, James A. Ross, Stephen J. Wigmore, Ewen M. Harrison

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 pretreatment 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 cotransfected to express TLR4 and a secreted alkaline phosphatase NF-ҡB reporter. Cells were pre-treated with AT13387 and exposed to endotoxin-free hyaluronan to stimulate sterile TLR4-specific NF-ҡB inflammatory activation. Following renal IRI, AT13387 significantly reduced serum creatinine, tubular necrosis, TLR4 expression and NF-ҡB-dependent chemokines. In vitro, AT13387-treatment resulted in breakdown of IҡB kinase, which abolished TLR4-mediated NF-ҡB activation by hyaluronan. AT13387 is a new agent with translational potential that reduces renal IRI. The mechanism of protection may involve breakdown of IҡB kinase and repression of TLR4-mediated NF-ҡB inflammatory activity.
Original languageEnglish
Article number12958
Number of pages11
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 7 Aug 2015

Keywords

  • ACUTE KIDNEY INJURY
  • ISCHEMIA/REPERFUSION INJURY
  • KINASE COMPLEX
  • IKK COMPLEX
  • ACTIVATION
  • HSP90
  • EXPRESSION
  • STRESS
  • TLR4
  • HEAT-SHOCK-PROTEIN-90

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