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Article

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
  • View Affiliations / Copyright

    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
  • Article Number: 393
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    Published online on: February 24, 2021
       https://doi.org/10.3892/etm.2021.9824
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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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1 

Prozialeck WC, Edwards JR, Nebert DW, Woods JM, Barchowsky A and Atchison WD: The vascular system as a target of metal toxicity. Toxicol Sci. 102:207–218. 2008.PubMed/NCBI View Article : Google Scholar

2 

Shinkai Y, Kimura T, Itagaki A, Yamamoto C, Taguchi K, Yamamoto M, Kumagai Y and Kaji T: Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells. Toxicol Appl Pharmacol. 295:37–46. 2016.PubMed/NCBI View Article : Google Scholar

3 

Zhai Q, Narbad A and Chen W: Dietary strategies for the treatment of cadmium and lead toxicity. Nutrients. 7:552–571. 2015.PubMed/NCBI View Article : Google Scholar

4 

Nair AR, Degheselle O, Smeets K, Van Kerkhove E and Cuypers A: Cadmium-induced pathologies: Where is the oxidative balance lost (or Not)? Int J Mol Sci. 14:6116–6143. 2013.PubMed/NCBI View Article : Google Scholar

5 

Aiba I, Hossain A and Kuo MT: Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Mol Pharmacol. 74:823–833. 2008.PubMed/NCBI View Article : Google Scholar

6 

Sun Z, Niu Z, Wu S and Shan S: Protective mechanism of sulforaphane in Nrf2 and anti-lung injury in ARDS rabbits. Exp Ther Med. 15:4911–4915. 2018.PubMed/NCBI View Article : Google Scholar

7 

Yang SH, Long M, Yu LH, Li L, Li P, Zhang Y, Guo Y, Gao F, Liu MD and He JB: Sulforaphane prevents testicular damage in Kunming mice exposed to cadmium via activation of Nrf2/ARE signaling pathways. Int J Mol Sci. 17(E1703)2016.PubMed/NCBI View Article : Google Scholar

8 

Alkharashi NAO, Periasamy VS, Athinarayanan J and Alshatwi AA: Sulforaphane mitigates cadmium-induced toxicity pattern in human peripheral blood lymphocytes and monocytes. Environ Toxicol Pharmacol. 55:223–239. 2017.PubMed/NCBI View Article : Google Scholar

9 

Sandbichler AM and Höckner M: Cadmium protection strategies--a hidden trade-off? Int J Mol Sci. 17(E139)2016.PubMed/NCBI View Article : Google Scholar

10 

Steele JW, Faulds D and Goa KL: Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus. Drugs Aging. 3:532–555. 1993.PubMed/NCBI View Article : Google Scholar

11 

Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M, Toyota T, Nakashima M, Yoshimura I, Sakamoto N, et al: Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care. 29:1538–1544. 2006.PubMed/NCBI View Article : Google Scholar

12 

Sato K, Yama K, Murao Y, Tatsunami R and Tampo Y: Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation. Redox Biol. 2:15–21. 2013.PubMed/NCBI View Article : Google Scholar

13 

Yama K, Sato K, Abe N, Murao Y, Tatsunami R and Tampo Y: Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells. Redox Biol. 4:87–96. 2015.PubMed/NCBI View Article : Google Scholar

14 

Luczak MW and Zhitkovich A: Role of direct reactivity with metals in chemoprotection by N-acetylcysteine against chromium(VI), cadmium(II), and cobalt(II). Free Radic Biol Med. 65:262–269. 2013.PubMed/NCBI View Article : Google Scholar

15 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔ C(T)) Method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar

16 

Tsukamoto M, Tampo Y, Sawada M and Yonaha M: Paraquat-induced oxidative stress and dysfunction of the glutathione redox cycle in pulmonary microvascular endothelial cells. Toxicol Appl Pharmacol. 178:82–92. 2002.PubMed/NCBI View Article : Google Scholar

17 

Zhou YJ, Zhang SP, Liu CW and Cai YQ: The protection of selenium on ROS mediated-apoptosis by mitochondria dysfunction in cadmium-induced LLC-PK(1) cells. Toxicol In Vitro. 23:288–294. 2009.PubMed/NCBI View Article : Google Scholar

18 

Meister A: Selective modification of glutathione metabolism. Science. 220:472–477. 1983.PubMed/NCBI View Article : Google Scholar

19 

Nair PMG, Park SY, Chung JW and Choi J: Transcriptional regulation of glutathione biosynthesis genes, γ-glutamyl-cysteine ligase and glutathione synthetase in response to cadmium and nonylphenol in Chironomus riparius. Environ Toxicol Pharmacol. 36:265–273. 2013.PubMed/NCBI View Article : Google Scholar

20 

Kolluru GK, Tamilarasan KP, Geetha Priya S, Durgha NP and Chatterjee S: Cadmium induced endothelial dysfunction: Consequence of defective migratory pattern of endothelial cells in association with poor nitric oxide availability under cadmium challenge. Cell Biol Int. 30:427–438. 2006.PubMed/NCBI View Article : Google Scholar

21 

Ono Pharmaceutical Co., Ltd., Kinedak® Tablets 50 mg. Epalrestat, Package Insert, Osaka, Japan, 2009.

22 

Harabawy AS and Mosleh YY: The role of vitamins A, C, E and selenium as antioxidants against genotoxicity and cytotoxicity of cadmium, copper, lead and zinc on erythrocytes of Nile tilapia, Oreochromis niloticus. Ecotoxicol Environ Saf. 104:28–35. 2014.PubMed/NCBI View Article : Google Scholar

23 

El-Boshy ME, Risha EF, Abdelhamid FM, Mubarak MS and Hadda TB: Protective effects of selenium against cadmium induced hematological disturbances, immunosuppressive, oxidative stress and hepatorenal damage in rats. J Trace Elem Med Biol. 29:104–110. 2015.PubMed/NCBI View Article : Google Scholar

24 

Mizuno K, Kume T, Muto C, Takada-Takatori Y, Izumi Y, Sugimoto H and Akaike A: Glutathione biosynthesis via activation of the nuclear factor E2-related factor 2 (Nrf2)--antioxidant-response element (ARE) pathway is essential for neuroprotective effects of sulforaphane and 6-(methylsulfinyl) hexyl isothiocyanate. J Pharmacol Sci. 115:320–328. 2011.PubMed/NCBI View Article : Google Scholar

25 

Jia Y, Lin J, Mi Y and Zhang C: Quercetin attenuates cadmium-induced oxidative damage and apoptosis in granulosa cells from chicken ovarian follicles. Reprod Toxicol. 31:477–485. 2011.PubMed/NCBI View Article : Google Scholar

26 

Bahar E, Kim JY and Yoon H: Quercetin attenuates manganese-induced neuroinflammation by alleviating oxidative stress through regulation of apoptosis, iNOS/NF-κB and HO-1/Nrf2 pathways. Int J Mol Sci. 18(E1989)2017.PubMed/NCBI View Article : Google Scholar

27 

Chen J and Shaikh ZA: Activation of Nrf2 by cadmium and its role in protection against cadmium-induced apoptosis in rat kidney cells. Toxicol Appl Pharmacol. 241:81–89. 2009.PubMed/NCBI View Article : Google Scholar

28 

Park JY and Seo YR: The protective role of Nrf2 in cadmium-induced DNA damage. Mol Cell Toxicol. 7:61–66. 2011. View Article : Google Scholar

29 

Leverrier P, Montigny C, Garrigos M and Champeil P: Metal binding to ligands: Cadmium complexes with glutathione revisited. Anal Biochem. 371:215–228. 2007.PubMed/NCBI View Article : Google Scholar

30 

Thévenod F and Lee WK: Cadmium and cellular signaling cascades: Interactions between cell death and survival pathways. Arch Toxicol. 87:1743–1786. 2013.PubMed/NCBI View Article : Google Scholar

31 

Himeno S, Yanagiya T and Fujishiro H: The role of zinc transporters in cadmium and manganese transport in mammalian cells. Biochimie. 91:1218–1222. 2009.PubMed/NCBI View Article : Google Scholar

32 

Dalton TP, He L, Wang B, Miller ML, Jin L, Stringer KF, Chang X, Baxter CS and Nebert DW: Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc Natl Acad Sci USA. 102:3401–3406. 2005.PubMed/NCBI View Article : Google Scholar

33 

Chen L, Ma L, Bai Q, Zhu X, Zhang J, Wei Q, Li D, Gao C, Li J, Zhang Z, et al: Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes. J Biol Chem. 289:22413–22426. 2014.PubMed/NCBI View Article : Google Scholar

34 

Murphy BJ, Andrews GK, Bittel D, Discher DJ, McCue J, Green CJ, Yanovsky M, Giaccia A, Sutherland RM, Laderoute KR, et al: Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. Cancer Res. 59:1315–1322. 1999.PubMed/NCBI

35 

Andrews GK: Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol. 59:95–104. 2000.PubMed/NCBI View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Tatsunami R, Sato K, Murao Y, Yama K, Yu Y, Ohno S and Tampo Y: Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells. Exp Ther Med 21: 393, 2021.
APA
Tatsunami, R., Sato, K., Murao, Y., Yama, K., Yu, Y., Ohno, S., & Tampo, Y. (2021). Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells. Experimental and Therapeutic Medicine, 21, 393. https://doi.org/10.3892/etm.2021.9824
MLA
Tatsunami, R., Sato, K., Murao, Y., Yama, K., Yu, Y., Ohno, S., Tampo, Y."Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells". Experimental and Therapeutic Medicine 21.4 (2021): 393.
Chicago
Tatsunami, R., Sato, K., Murao, Y., Yama, K., Yu, Y., Ohno, S., Tampo, Y."Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells". Experimental and Therapeutic Medicine 21, no. 4 (2021): 393. https://doi.org/10.3892/etm.2021.9824
Copy and paste a formatted citation
x
Spandidos Publications style
Tatsunami R, Sato K, Murao Y, Yama K, Yu Y, Ohno S and Tampo Y: Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells. Exp Ther Med 21: 393, 2021.
APA
Tatsunami, R., Sato, K., Murao, Y., Yama, K., Yu, Y., Ohno, S., & Tampo, Y. (2021). Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells. Experimental and Therapeutic Medicine, 21, 393. https://doi.org/10.3892/etm.2021.9824
MLA
Tatsunami, R., Sato, K., Murao, Y., Yama, K., Yu, Y., Ohno, S., Tampo, Y."Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells". Experimental and Therapeutic Medicine 21.4 (2021): 393.
Chicago
Tatsunami, R., Sato, K., Murao, Y., Yama, K., Yu, Y., Ohno, S., Tampo, Y."Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells". Experimental and Therapeutic Medicine 21, no. 4 (2021): 393. https://doi.org/10.3892/etm.2021.9824
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