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KMID : 0811720180220020135
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Korean Journal of Physiology & Pharmacology
2018 Volume.22 No. 2 p.135 ~ p.143
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Tumor necrosis factor α-converting enzyme inhibitor attenuates lipopolysaccharide-induced reactive oxygen species and mitogen-activated protein kinase expression in human renal proximal tubule epithelial cells
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Bae Eun-Hui
Kim In-Jin
Choi Hong-Sang
Kim Ha-Yeon
Kim Chang-Seong
Ma Seong-Kwon
Kim In-S.
Kim Soo-Wan
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Abstract
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Tumor necrosis factor-α (TNFα) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which TNFα-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, TNFα, 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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KEYWORD
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Acute kidney injury, Angiotensin-converting enzyme-2, Lipopolysaccharide, Mitogen activated protein kinase, Oxidative stress, TNFα-converting enzyme
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