TITLE:
TNF Type-I Receptor Inhibitor, R-7050 Attenuates Acute Kidney Injury in a Mouse Model of Crush Syndrome
AUTHORS:
Shinya Mizuno, Eriko Osaki, Hiroyuki Ohnishi
KEYWORDS:
AKI, Hyperkalemia, IL-6, Rhabdomyolysis, TNF-α
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.9 No.12,
December
29,
2018
ABSTRACT: 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.