PGC-1α attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38 in HK-2 Cells
Abstract Ischemia/reperfusion injury triggers acute kidney injury (AKI) by aggravating oxidative stress mediated mitochondria dysfunction. The peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master player that regulates mitochondrial biogenesis and the antioxidant respo...
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| Autores principales: | , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/f29a45800068461394321d8111c6f414 |
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| Sumario: | Abstract Ischemia/reperfusion injury triggers acute kidney injury (AKI) by aggravating oxidative stress mediated mitochondria dysfunction. The peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master player that regulates mitochondrial biogenesis and the antioxidant response. We postulated that PGC-1α 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-1α, we developed an empty vector or PGC-1α-overexpressing stable cell lines in HK-2 cells (Mock or PGC-1α stable cells). PGC-1α 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-1α 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 3β (GSK3β)/Nrf-2 axis was involved in the protective effects of PGC-1α. Taken together, we suggest that PGC-1α protects human renal tubule cells from H2O2-mediated apoptotic injury by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38. |
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