Abstract
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).
Highlights
Cisplatin is an inorganic platinum chemotherapy drug that is commonly used in clinical chemotherapy treatment (Yang et al, 2018) because it can effectively treat a wide range of solid tumors, including lung, ovarian, and bladder cancers
Primary antibodies against nuclear factor erythrocyte 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1), P53, caspase-3, Bax, Bcl2, phospho-Jun N-terminal kinase (JNK), phospho-extracellular signal-regulated kinase (ERK), phospho-p38, and NF-κB were purchased from Abcam (Cambridge, MA, USA) and Cell Signaling (Boston, MA, USA)
To identify the signals involved in the effects, we initially focused on reactive oxygen species (ROS), which are associated with cisplatin nephrotoxicity
Summary
Cisplatin is an inorganic platinum chemotherapy drug that is commonly used in clinical chemotherapy treatment (Yang et al, 2018) because it can effectively treat a wide range of solid tumors, including lung, ovarian, and bladder cancers. Cisplatin has many serious side effects, such as myelosuppression, nephrotoxicity, and ototoxicity (Stojic et al, 2018), and these toxic side effects limit the clinical application of cisplatin as part of standard cancer treatment. AKI treatment is mainly supportive, and there is no treatment with curative effects (Bagshaw and Wald, 2016). The current diagnostic criteria include the BUN and SCr levels, which primarily reflect the late manifestations of the disease, and early intervention is critical for the effective treatment of AKI (Moledina and Parikh, 2018; Fu et al, 2019)
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