Epalrestat Suppresses Cadmium-induced Cytotoxicity Through Nrf2 in Endothelial Cells

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2021 Mar 8

PMID 33680115

Citations 1

Authors

Ryosuke Tatsunami

Keisuke Sato

Yu Murao

Kaori Yama

Yang Yu

Shun Ohno

Yoshiko Tampo

Affiliations

Soon will be listed here.

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.

Citing Articles

[Cadmium polyneuropathy: a rare, but not less important, cause of peripheral neuropathy].

Leon-Ruiz M, Jimenez-Jimenez F, Benito-Leon J Rev Neurol. 2022; 74(12):403-407.

PMID: 35698435 PMC: 11502201. DOI: 10.33588/rn.7412.2021288.

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