Triptolide induces oxidative damage in NRK-52E cells through facilitating Nrf2 degradation by ubiquitination via the...

Area of Science:

• Pharmacology
• Toxicology
• Molecular Biology

Background:

• Triptolide (TP), derived from Tripterygium wilfordii Hook F. (TWHF), exhibits potent anti-inflammatory, immunosuppressive, and anti-tumor activities.
• However, its clinical application is severely limited by significant side effects, particularly nephrotoxicity.

Purpose of the Study:

• To investigate the role of the GSK-3β/Fyn signaling pathway in Triptolide-induced oxidative kidney damage.
• To elucidate the mechanism underlying Triptolide's downregulation of Nrf2 protein.

Main Methods:

• Utilized the rat renal tubular epithelial cell line NRK-52E.
• Assessed oxidative stress, cell damage, protein degradation, and apoptosis.
• Employed GSK-3β inhibitors (lithium chloride) and proteasome inhibitors (MG132).

Main Results:

• Triptolide activated GSK-3β and promoted Fyn nuclear translocation, decreasing Nrf2 nuclear translocation and inducing oxidative stress and cell damage.
• Triptolide enhanced Nrf2 degradation via ubiquitination, a process inhibited by MG132.
• GSK-3β inhibition with lithium chloride restored Nrf2 nuclear translocation, reduced Fyn translocation, and mitigated cell damage, LDH leakage, glutathione depletion, and apoptosis.

Conclusions:

• Triptolide induces oxidative kidney damage in NRK-52E cells by promoting Nrf2 degradation through ubiquitination.
• The GSK-3β/Fyn pathway is a key mediator of Triptolide-induced nephrotoxicity.
• Targeting the GSK-3β/Fyn pathway may offer a therapeutic strategy to mitigate Triptolide's adverse effects.