Abstract
Disrupted redox homeostasis contributes to renal ischemia–reperfusion (IR) injury. Abundant natural products can activate nuclear factor erythroid-2-related factor 2 (Nrf2), thereby providing therapeutic benefits. Methyl eugenol (ME), an analog of the phenolic compound eugenol, has the ability to induce Nrf2 activity. In this study, we investigated the protective effects of ME against renal oxidative damage in vivo and in vitro. An IR-induced acute kidney injury (AKI) model was established in mice. ME (20 mg·kg−1·d−1, i.p.) was administered to mice on 5 consecutive days before IR surgery. We showed that ME administration significantly attenuated renal destruction, improved the survival rate, reduced excessive oxidative stress and inhibited mitochondrial lesions in AKI mice. We further demonstrated that ME administration significantly enhanced Nrf2 activity and increased the expression of downstream antioxidative molecules. Similar results were observed in vitro in hypoxia/reoxygenation (HR)-exposed proximal tubule epithelial cells following pretreatment with ME (40 μmol·L−1). In both renal oxidative damage models, ME induced Nrf2 nuclear retention in tubular cells. Using specific inhibitors (CC and DIF-3) and molecular docking, we demonstrated that ME bound to the binding pocket of AMPK with high affinity and activated the AMPK/GSK3β axis, which in turn blocked the Nrf2 nuclear export signal. In addition, ME alleviated the development of renal fibrosis induced by nonfatal IR, which is frequently encountered in the clinic. In conclusion, we demonstrate that ME modulates the AMPK/GSK3β axis to regulate the cytoplasmic–nuclear translocation of Nrf2, resulting in Nrf2 nuclear retention and thereby enhancing antioxidant target gene transcription that protects the kidney from oxidative damage.
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Acknowledgements
The present study was supported by grants from the National Natural Science Foundation of China (grant nos. 82170772, 81873623 and 81570678), the Major State Basic Research Development Program of China (grant no. 2013CB530803), the Clinical Research Physician Program of Tongji Medical College, HUST and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences (grant no. 2018PT32018). The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn/) for expert linguistic services.
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BCK and ZHW performed the experiments, analyzed the data, and wrote the draft. SHH, MQW, and KLS performed the experiments and assisted in data interpretation. JZ, JSZ, and HQN helped with the acquisition of samples and data collection. NQG designed the study and edited the manuscript. All authors read and approved the final paper.
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Kuang, Bc., Wang, Zh., Hou, Sh. et al. Methyl eugenol protects the kidney from oxidative damage in mice by blocking the Nrf2 nuclear export signal through activation of the AMPK/GSK3β axis. Acta Pharmacol Sin 44, 367–380 (2023). https://doi.org/10.1038/s41401-022-00942-2
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DOI: https://doi.org/10.1038/s41401-022-00942-2
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