Abstract
Purpose: To investigate the effect of Z-ligustilide (Z-lig) on cisplatin-induced nephrotoxicity and examine whether NRF2 signaling mediates the underlying mechanism of action.Methods: Human proximal tubular epithelial cells (HK-2) were pretreated with 20 or 100 μM Z-lig for 2 h, followed by 10 μM cisplatin treatment for 24 h. Cell viability was measured using (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A commercial kit was used todetermine lactate dehydrogenase (LDH) release. Apoptosis was determined by flow cytometry while Western blotting was used to evaluate protein levels. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) were assessed by enzymelinked immunosorbent assay (ELISA).Results: Cisplatin decreased HK-2 cell viability and increased LDH release, while Z-lig increased cell viability and decreased LDH release in a dose-dependent manner (p < 0.05). Moreover, Z-lig reduced cisplatin-induced apoptosis (p < 0.01), and alleviated cellular oxidative stress caused by cisplatin (p < 0.05). Furthermore, Z-lig activated NRF2/HO-1 signaling in cells treated with cisplatin (p < 0.05).Conclusion: Z-lig reduces cisplatin-induced nephrotoxicity via activation of NRF2/HO-1 signaling. Thus, Z-lig is a potential drug for the treatment of nephrotoxicity caused by cisplatin.
 Keywords: Z-ligustilide, Cisplatin, Nephrotoxicity, Oxidative stress, Apoptosis, Nuclear factor erythroid 2-related factor 2, Heme oxygenase-1
Highlights
Cisplatin is a primary chemotherapy drug used to treat various cancers [1]
To elucidate the effect of Z-lig on nephrotoxicity caused by cisplatin, we first assessed cell viability and lactate dehydrogenase (LDH) release by HK-2 cells that had been treated with Z-lig or cisplatin
100 μM Z-lig alone did not alter cell viability or LDH leakage (Figures 1 B and C). These results indicated that Z-lig was nontoxic to the cells, and that Z-lig reduced cellular injury caused by cisplatin
Summary
Cisplatin is a primary chemotherapy drug used to treat various cancers [1]. Nephrotoxicity limits the use of cisplatin [2]. Previous studies revealed that over 30% of patients present symptoms of acute renal injury following cisplatin administration [3,4]. The mechanism of cisplatin-induced nephrotoxicity is related to many factors, such as cellular oxidative stress, mitochondrial dysfunction, and apoptosis [5]. Oxidative stress is considered to be an important factor leading to cisplatin nephrotoxicity [6]. Nuclear factor erythroid 2-related factor 2 (NRF2) is involved in oxidative stress [7]
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