Methyl eugenol protects the kidney from oxidative damage in mice by blocking the Nrf2 nuclear export signal through activation of the AMPK/GSK3β axis

Bai-cheng Kuang1, Zhi-heng Wang1, Shuai-heng Hou1, Ji Zhang1,2, Meng-qin Wang1, Jia-si Zhang1, Kai-lun Sun1, Hai-qiang Ni1, Nian-qiao Gong1
1 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan 430030, China
2 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, China
Correspondence to: Nian-qiao Gong:,
DOI: 10.1038/s41401-022-00942-2
Received: 16 March 2022
Accepted: 8 June 2022
Advance online: 6 July 2022


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.
Keywords: methyl eugenol; acute kidney injury; oxidative damage; Nrf2; AMPK/GSK3β; proximal tubule epithelial cells

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