Crush syndrome (CS) is caused by severe and extensive muscular skeletal damages, and acute kidney injury (AKI) with hyperkalemia is one of the most lethal factors of this syndrome. Especially under natural disasters of earthquake, many persons die due to AKI and hyperkalemia-induced cardiac arrest, but there has been no pathogenesis-based drugs for preventing CS-induced AKI. Pro-inflammatory cytokines, such as TNF- α and IL-6, play a critical role for induction of AKI during CS development. Glycerol-injected mice are used as an experimental tool for reflecting pathological events of human CS. Using this popular model, we provide evidence to show that TNF type-I receptor (TNFR1) inhibitor, R-7050 significantly attenuates the onset of AKI after the muscular destruction. In this process, R-7050 treatment suppressed the NF-κB activation in the affected kidney, and this was associated with a decrease in blood IL-6, a downstream target of NF-κB. As a result, renal tubular apoptosis became milder in the R-7050-treated CS mice. These findings suggest that induction of IL-6 via sequential events of TNF- α à TNFR1 à NF - κB is contributable for renal tubular apoptosis, a histological hallmark of AKI. Thus, TNFR1-selective inhibition can be a pharmacological strategy to attenuate the onset of AKI immediately after the clinical manifestation of rhabdomyolysis.
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