Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells

Tatsunami,Ryosuke; Sato,Keisuke; Murao,Yu; Yama,Kaori; Yu,Yang; Ohno,Shun; Tampo,Yoshiko

doi:10.3892/etm.2021.9824

Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells

Authors:
- Ryosuke Tatsunami
- Keisuke Sato
- Yu Murao
- Kaori Yama
- Yang Yu
- Shun Ohno
- Yoshiko Tampo
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Affiliations: Department of Pharmacy, Hokkaido University of Science, Sapporo, Hokkaido 006-8585, Japan, China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China
Published online on: February 24, 2021 https://doi.org/10.3892/etm.2021.9824
Article Number: 393

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Abstract

Cadmium (Cd) is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by Cd toxicity. Recent studies have indicated an association between Cd and vascular diseases, although the mechanisms of Cd implications in vascular diseases are not clear. The purpose of the present study was to determine whether epalrestat (EPS), which is used for the treatment of diabetic neuropathy, protects against Cd-induced cytotoxicity in bovine aortic endothelial cells (BAECs). In the present study, the effects of EPS at near-plasma concentration were examined on Cd-induced cytotoxicity in BAECs. Cd-induced cytotoxicity was suppressed by pretreatment with EPS. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that serves a role in regulating the expression of glutamate cysteine ligase, the rate-limiting enzyme in glutathione (GSH) synthesis. In a previous study, EPS was demonstrated to increase GSH levels in BAECs in association with the Nrf2 pathway. In the present study, EPS increased GSH levels in BAECs exposed to Cd. The protective ability of EPS against the Cd-induced cytotoxicity disappeared following Nrf2 small interfering RNA transfection. In addition, EPS affected the intracellular levels of Cd, Cd transporter ZIP8 and metallothionein. To the best of our knowledge, the current study demonstrated, for the first time, that EPS suppresses Cd-induced cytotoxicity in BAECs. The upregulation of GSH may be associated with the suppression of Cd-induced cytotoxicity by EPS. From these ﬁndings, it may be proposed that the regulation of GSH, ZIP8 and metallothionein by EPS is a promising therapeutic approach to prevent Cd-induced toxicity.

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