1. Academic Validation
  2. Fraxetin pretreatment alleviates cisplatin-induced kidney injury by antagonizing autophagy and apoptosis via mTORC1 activation

Fraxetin pretreatment alleviates cisplatin-induced kidney injury by antagonizing autophagy and apoptosis via mTORC1 activation

  • Phytother Res. 2024 Apr;38(4):2077-2093. doi: 10.1002/ptr.8073.
Ziwei Yuan 1 Xuejia Yang 1 Zujian Hu 1 Yuanyuan Gao 1 Mengsi Wang 1 Lili Xie 1 Hengyue Zhu 2 Chaosheng Chen 3 4 Hong Lu 5 Yongheng Bai 1 4
Affiliations

Affiliations

  • 1 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 4 Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou, China.
  • 5 Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Abstract

Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC. bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs Autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased Autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced Apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on Apoptosis and Autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In summary, fraxetin pretreatment alleviates CKI by antagonizing Autophagy and Apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.

Keywords

apoptosis; autophagy; cisplatin; fraxetin; mTORC1; renal injury.

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