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

• Published in: Scientific reports 2015-08, Vol.5 (1), p.12958-12958, Article 12958
• Main Authors: O’Neill, Stephen, Humphries, Duncan, Tse, George, Marson, Lorna P., Dhaliwal, Kevin, Hughes, Jeremy, Ross, James A., Wigmore, Stephen J, Harrison, Ewen M.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 64/60; 692/308/1426; 692/699/1585/4; Alkaline Phosphatase - metabolism; Animals; Benzamides - pharmacology; Cell Line; HEK293 Cells; HSP90 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; I-kappa B Kinase - metabolism; Inflammation - metabolism; Isoindoles - pharmacology; Kidney - metabolism; Male; Mice; multidisciplinary; NF-kappa B - metabolism; Reperfusion Injury - metabolism; Science; Signal Transduction - drug effects; Signal Transduction - physiology; Toll-Like Receptor 4 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep12958

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.