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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.01419

Farrerol Attenuates Cisplatin-Induced Nephrotoxicity by Inhibiting the ROS-Mediated Oxidation, Inflammation and Apoptotic Signaling Pathways

 Ning Ma1,  Wei Wei1, Xiaoye Fan2 and  Xinxin Ci2*
  • 1Department of Urology, The First Hospital of Jilin University, China
  • 2Institute of Translational Medicine, The First Hospital of Jilin University, China

Cisplatin is a chemotherapy drug that is often used in clinical practice, but its frequent use often leads to nephrotoxicity. Therefore, we urgently need a drug that reduces the nephrotoxicity induced by cisplatin. Farrerol reportedly has antioxidant potential, but its renal protective effects and potential mechanisms remain unclear. In this study, we used both cell and mouse models to determine the mechanism of farrerol in cisplatin-induced nephrotoxicity. The in vitro experiments revealed that farrerol improved cisplatin-induced nephrotoxicity and reactive oxygen species (ROS) production via nuclear factor erythrocyte 2-related factor 2 (Nrf2) activation. Moreover, farrerol effectively activated Nrf2 and subsequently increased the expression of Nrf2-targeted antioxidant enzymes, including heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1), but inhibited Kelch-like ECH-associated protein 1 (Keap1) and NADPH oxidase type 4 (NOX4). Furthermore, farrerol attenuated the phosphorylation of C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38), the activation of phosphorylated nuclear factor-κB (p-NF-κB) and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), and the expression of phosphorylated p53 (p-p53), Bax and cleaved caspase-3. In vivo, farrerol significantly improved cisplatin-induced renal damage, as demonstrated by the recovery of blood urea nitrogen (BUN), serum creatinine (SCr), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and pathological damage. Moreover, farrerol inhibited inflammatory and apoptotic protein expression in vivo. Notably, farrerol exerted slight protection in Nrf2-knockout mice compared with wild-type mice. These findings indicate that farrerol can effectively activate Nrf2 and can serve as a therapeutic target in the treatment of acute kidney injury (AKI).

Keywords: Farrerol, Cisplatin, Oxidative Stress, ROS, Nrf2, Inflammation, Apotosis, AKI

Received: 18 Jul 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 Ma, Wei, Fan and Ci. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Xinxin Ci, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province, China, cixinxin@jlu.edu.cn