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2017 ; 130
(18
): 2163-2169
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Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear
Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury
#MMPMID28836571
Huang RS
; Zhou JJ
; Feng YY
; Shi M
; Guo F
; Gou SJ
; Salerno S
; Ma L
; Fu P
Chin Med J (Engl)
2017[Sep]; 130
(18
): 2163-2169
PMID28836571
show ga
BACKGROUND: Acute kidney injury (AKI) is the most common and life-threatening
systemic complication of rhabdomyolysis. Inflammation plays an important role in
the development of rhabdomyolysis-induced AKI. This study aimed to investigate
the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage
Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-?B) signaling pathway.
METHODS: C57BL/6 mice were injected with a 50% glycerin solution at bilateral
back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate
(PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine
levels, creatine kinase, the expression of tumor necrosis factor (TNF)-?,
interleukin (IL)-1? and IL-6, and hematoxylin and eosin stainings of kidney
tissues were tested. The infiltration of macrophage, mRNA levels, and protein
expression of TLR4 and NF-?B were investigated by immunofluorescence
double-staining techniques, reverse transcriptase-quantitative polymerase chain
reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was
stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-?B expressions were
also detected. RESULTS: In an in vivo study, using CLI-095 or PDTC to block
TLR4/NF-?B, functional and histologic results showed that the inhibition of TLR4
or NF-?B alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC
administration suppressed proinflammatory cytokine (TNF-?, IL-6, and IL-1?)
production and macrophage infiltration into the kidney (P < 0.01). Moreover, in
an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of
TLR4, NF-?B, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P
< 0.01). CONCLUSION: The pharmacological inhibition of TLR4/NF-?B exhibited
protective effects on rhabdomyolysis-induced AKI by the regulation of
proinflammatory cytokine production and macrophage infiltration.