Tumor necrosis factor ?-converting enzyme inhibitor attenuates
lipopolysaccharide-induced reactive oxygen species and mitogen-activated protein
kinase expression in human renal proximal tubule epithelial cells
#MMPMID29520166
Bae EH
; Kim IJ
; Choi HS
; Kim HY
; Kim CS
; Ma SK
; Kim IS
; Kim SW
Korean J Physiol Pharmacol
2018[Mar]; 22
(2
): 135-143
PMID29520166
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Tumor necrosis factor-? (TNF?) and the angiotensin system are involved in
inflammatory diseases and may contribute to acute kidney injury. We investigated
the mechanisms by which TNF?-converting enzyme (TACE) contributes to
lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE
inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule
epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2
cells were cultured with or without LPS (10 µg/ml) in the presence or absence of
a type 1 TACE inhibitor (1 µM) or type 2 TACE inhibitor (10 µM). LPS treatment
induced increased serum creatinine, TNF?, and urinary neutrophil
gelatinase-associated lipocalin. Angiotensin II type 1 receptor, mitogen
activated protein kinase (MAPK), and TACE increased, while angiotensin-converting
enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and
LPS-treated HK-2 cells. LPS induced reactive oxygen species and the
down-regulation of ACE2, and these responses were prevented by TACE inhibitors in
HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells
and attenuated oxidative stress and inflammatory cytokines. Our findings indicate
that LPS activates renin angiotensin system components via the activation of
TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney
injury.
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