PGC-1α attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38 in HK-2 Cells

被引:96
作者
Choi, Hoon-In [1 ]
Kim, Hye-Jin [1 ]
Park, Jung-Sun [1 ]
Kim, In-Jin [1 ]
Bae, Eun Hui [1 ]
Ma, Seong Kwon [1 ]
Kim, Soo Wan [1 ]
机构
[1] Chonnam Natl Univ, Med Sch, Dept Internal Med, Gwangju, South Korea
基金
新加坡国家研究基金会;
关键词
RECEPTOR-GAMMA COACTIVATOR-1; PPAR-GAMMA; MITOCHONDRIAL DYSFUNCTION; TRANSCRIPTION FACTORS; N-ACETYLCYSTEINE; OXIDATIVE STRESS; HEME OXYGENASE-1; SMOOTH-MUSCLE; TISSUE-INJURY; BETA-TRCP;
D O I
10.1038/s41598-017-04593-w
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Ischemia/reperfusion injury triggers acute kidney injury (AKI) by aggravating oxidative stress mediated mitochondria dysfunction. The peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a master player that regulates mitochondrial biogenesis and the antioxidant response. We postulated that PGC-1 alpha functions as cytoprotective effector in renal cells and that its regulation mechanism is coordinated by nuclear factor erythroid 2-related factor 2 (Nrf-2). In this study, to understand the effect and molecular mechanisms of PGC-1 alpha, we developed an empty vector or PGC-1 alpha-overexpressing stable cell lines in HK-2 cells (Mock or PGC-1 alpha stable cells). PGC-1 alpha overexpression increased the viability of cells affected by H2O2 mediated injury, protected against H2O2-mediated apoptotic events and inhibited reactive oxygen species accumulation in the cytosol and mitochondria as compared to that in Mock cells. The cytoprotective effect of PGC-1 alpha was related to Nrf-2 upregulation, which was counteracted by Nrf-2-specific knockdown. Using inhibitor of p38, we found that regulation of the p38/glycogen synthase kinase 3 beta (GSK3 beta)/Nrf-2 axis was involved in the protective effects of PGC-1 alpha. Taken together, we suggest that PGC-1 alpha protects human renal tubule cells from H2O2-mediated apoptotic injury by upregulating Nrf-2 via GSK3 beta inactivation mediated by activated p38.
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页数:13
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