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.