2. Academic Validation
  3. Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis

Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis

  • Toxicol Appl Pharmacol. 2023 Jun 14;473:116595. doi: 10.1016/j.taap.2023.116595.
Zheming Xu 1,  Minjing Zhang 1,  Wenwen Wang 2,  Suhan Zhou 3,  Minghua Yu 4,  Xingyu Qiu 3,  Shan Jiang 5,  Xiaohua Wang 5,  Chun Tang 5,  Shuijie Li 6,  Chih-Hong Wang 7,  Runzhi Zhu 1,  Wan Xin Peng 1,  Lin Zhao 1,  Xiaodong Fu 8,  Andreas Patzak 9,  Pontus B Persson 9,  Liang Zhao 10,  Jianhua Mao 10,  Qiang Shu 11,  En Yin Lai 12,  Gensheng Zhang 13
Affiliations

Affiliations

  • 1 Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou 310052, China.
  • 2 Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310051, China.
  • 3 Department of Physiology, School of Basic Medical Sciences, and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
  • 5 Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China.
  • 6 Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 7 Tulane Hypertension and Renal Center of Excellence, Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA.
  • 8 Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 510260, China.
  • 9 Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Translational Physiology, Berlin, Germany.
  • 10 Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou 310052, China; Children's Hospital, Zhejiang University School of Medicine, Pediatric Nephrology & Urology Medical Research Center, Hangzhou 310052, China.
  • 11 Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou 310052, China. Electronic address: [email protected].
  • 12 Department of Physiology, School of Basic Medical Sciences, and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Translational Physiology, Berlin, Germany. Electronic address: [email protected].
  • 13 Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou 310052, China; Children's Hospital, Zhejiang University School of Medicine, Pediatric Nephrology & Urology Medical Research Center, Hangzhou 310052, China. Electronic address: [email protected].
PMID: 37328118 DOI: 10.1016/j.taap.2023.116595
Abstract

Background: Cisplatin is effective against various types of cancers. However, its clinical application is limited owing to its adverse effects, especially acute kidney injury (AKI). Dihydromyricetin (DHM), a flavonoid derived from Ampelopsis grossedentata, has varied pharmacological activities. This research aimed to determine the molecular mechanism for cisplatin-induced AKI.

Methods: A murine model of cisplatin-induced AKI (22 mg/kg, I.P.) and a HK-2 cell model of cisplatin-induced damage (30 μM) were established to evaluate the protective function of DHM. Renal dysfunction markers, renal morphology and potential signaling pathways were investigated.

Results: DHM decreased the levels of renal function biomarkers (blood urea nitrogen and serum creatinine), mitigated renal morphological damage, and downregulated the protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. It upregulated the expression levels of antioxidant enzymes (superoxide dismutase and catalase expression), nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream proteins, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunits, thus eventually reducing cisplatin-induced Reactive Oxygen Species (ROS) production. Moreover, DHM partially inhibited the phosphorylation of the active fragments of Caspase-8 and -3 and mitogen-activated protein kinase and restored Glutathione Peroxidase 4 expression, which attenuated renal Apoptosis and Ferroptosis in cisplatin-treated Animals. DHM also mitigated the activation of NLRP3 inflammasome and nuclear factor (NF)-κB, attenuating the inflammatory response. In addition, it reduced cisplatin-induced HK-2 cell Apoptosis and ROS production, both of which were blocked by the Nrf2 inhibitor ML385.

Conclusions: DHM suppressed cisplatin-induced oxidative stress, inflammation and Ferroptosis probably through regulating of Nrf2/HO-1, MAPK and NF-κB signaling pathways.

Keywords

Acute Kidney Injury; Cisplatin; Dihydromyricetin; Inflammation; Oxidative Stress.

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