Journal
TOXICOLOGY IN VITRO
Volume 58, Issue -, Pages 187-194Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2019.03.032
Keywords
Triptolide; Oxidative stress; GSK-3 beta; Nrf2; Ubiquitination
Categories
Funding
- Natural Science Foundation For Young Scientists of China [81603212]
- Project for Municipal Universities in Guangzhou [1201630109]
- Guangzhou Medical Science & Technology Project [20171A011319]
- General Projects in the Natural Science Foundation of Guangdong Province [2018A0303130170]
- National Natural Science Foundation of China [81773992]
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Triptolide (TP) isolated from Tripterygium wilfordii Hook F. (TWHF) shows extensive anti-inflammation, immunosuppression and anti-tumor properties. However, its therapeutic potential is limited by its severe side effects, especially the nephrotoxicity. This study intended to explore the role of the GSK-3 beta/Fyn pathway in TP-induced oxidative damage and the potential mechanism of Nrf2 protein downregulation. Our data showed that TP induced oxidative stress and cell damage in the rat renal tubular epithelial cell line NRK-52E cells by activation of GSK-3 beta and nuclear translocation of Fyn, which resulted in decreased Nrf2 nuclear translocation. Moreover, TP significantly induced Nrf2 degradation by ubiquitination, which was blocked by the proteasome inhibitor MG132. In addition, cotreatment with a typical GSK-3 beta inhibitor, lithium chloride, promoted the nuclear translocation of Nrf2 and decreased the nuclear translocation of Fyn, which led to reduced cell damage, LDH leakage, glutathione depletion and cell apoptosis. Collectively, our results indicated that TP induced oxidative damage in NRK-52E cells by facilitating Nrf2 degradation by ubiquitination via the GSK-3 beta/Fyn pathway.
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