Zinc supplementation inhibits the high glucose‑induced EMT of peritoneal mesothelial cells by activating the Nrf2 antioxidant pathway

Gao,Lili; Fan,Yi; Zhang,Xiuli; Yang,Lina; Huang,Wenyu; Hang,Tianyu; Li,Mingyang; Du,Shuyan; Ma,Jianfei

doi:10.3892/mmr.2019.10260

Zinc supplementation inhibits the high glucose‑induced EMT of peritoneal mesothelial cells by activating the Nrf2 antioxidant pathway

Authors:
- Lili Gao
- Yi Fan
- Xiuli Zhang
- Lina Yang
- Wenyu Huang
- Tianyu Hang
- Mingyang Li
- Shuyan Du
- Jianfei Ma
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Affiliations: Department of Nephrology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: May 22, 2019 https://doi.org/10.3892/mmr.2019.10260
Pages: 655-663
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The high glucose (HG)‑induced epithelial‑mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) serves an important role in peritoneal fibrosis (PF) during peritoneal dialysis. Our previous study reported that zinc (Zn) supplementation prevented the HG‑induced EMT of rat PMCs in vitro. In the present study, the role of Zn in HG‑induced EMT was investigated in vivo using a rat model of PF. Additionally, the molecular mechanisms underlying HG‑induced EMT were studied in human PMCs (HPMCs). In the rat model of PF, HG treatment increased the glucose transfer capacity and decreased the ultrafiltration volume. Histopathological analysis revealed peritoneal thickening, increased expression of vimentin and decreased expression of E‑cadherin. ZnSO4 significantly ameliorated the aforementioned changes, whereas Zn inhibition by clioquinol significantly aggravated the effects of HG on rats. The effects of Zn on HPMCs was assessed using western blot analysis, Transwell assays and flow cytometry. It was revealed that Zn also signiﬁcantly suppressed the extent of the EMT, and reduced reactive oxygen species production and the migratory ability of HG‑induced HPMCs, whereas Zn inhibition by N',N',N',N'‑tetrakis (2‑pyridylmethyl) ethylenediamine significantly potentiated the HG‑induced EMT of HPMCs. HG‑stimulated HPMCs exhibited increased expression of nuclear factor‑like 2 (Nrf2) in the nucleus, and total cellular NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase-1 (HO‑1), the target proteins of the Nrf2 antioxidant pathway. Zn supplementation further promoted nuclear Nrf2 expression, and increased the expression of target proteins of the Nrf2 antioxidant pathway, whereas Zn depletion decreased nuclear Nrf2, NQO1 and HO‑1 expression compared with the HG group. In conclusion, Zn supplementation was proposed to suppress the effects of HG on the EMT by stimulating the Nrf2 antioxidant pathway and subsequently reducing oxidative stress in PMCs.

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