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TRPA1 promotes cisplatin-induced nephrotoxicity through inflammation mediated by the MAPK/NF-κB signaling pathway.

Authors
  • Yuan, Jinyan1, 2
  • Liang, Xiao3
  • Zhou, Wei2
  • Feng, Jing4
  • Wang, Zhenyang1, 2
  • Shen, Shaoxian5
  • Guan, Xin5
  • Zhao, Liangbin6
  • Deng, Fei1, 5
  • 1 Department of Nephrology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. , (China)
  • 2 School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. , (China)
  • 3 Department of Internal Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. , (China)
  • 4 Department of Traditional Chinese Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. , (China)
  • 5 Department of Nephrology, Jinniu Hospital of Sichuan Provincial People's Hospital and Chengdu Jinniu District People's Hospital, Chengdu, China. , (China)
  • 6 Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. , (China)
Type
Published Article
Journal
Annals of Translational Medicine
Publisher
AME Publishing Company
Publication Date
Oct 01, 2021
Volume
9
Issue
20
Pages
1578–1578
Identifiers
DOI: 10.21037/atm-21-5125
PMID: 34790784
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The nephrotoxicity induced by cisplatin (DDP) has been a severe obstacle for its clinical use in anticancer treatment. The apoptosis and inflammation induced by DDP are the main causes of the nephrotoxicity. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation ligand-gated channel that is involved in the inflammation progress. The apoptosis, inflammation, MAPK/NF-κB signaling pathway, and TRPA1 expression were assessed after HEK293 cells had been induced by DDP, and the role of TRPA1 in apoptosis and inflammation of DDP-induced HEK293 cells treated with TRPA1 antagonist HC-030031 was also evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot assays. The cell viability was reduced by DDP in both a time-dependent and dose-dependent manner with a minimal cytotoxic concentration of 10 μM. Moreover, DDP induced an enhancement of the apoptosis and inflammation in a dose-dependent manner, as indicated by the increase of the relative protein level of cleaved-caspase3 (cleaved-cas3), the cleavage product of caspase-3 substrate poly-ADP-ribose polymerase (cleaved-PARP) and inducible nitric oxide synthase (iNOS), and the messenger RNA (mRNA) expression level of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ). Additionally, DDP treatment increased the protein phosphorylation expression of IKKβ, JNK, ERK, and p38 in a dose-dependent manner, which was antagonized by the treatment of NF-κB-specific inhibitor BAY 11-7082 and pan-MAPK inhibitor U0126. It was also found that DDP upregulated the expression of TRPA1 at both the mRNA and protein levels in a dose-dependent manner. Besides, block of TRPA1 with HC-030031 relieved the apoptosis, diminished the level of IL-1β, IL-6, TNF-α, and INF-γ, reduced the level of cleaved-cas3, cleaved-PARP, and iNOS, decreased the p-IKKβ, p-JNK, p-ERK, and p-p38 expression, and enhanced the expression of IκBα. Taken together, these results indicate that TRPA1 regulates DDP-induced nephrotoxicity via inflammation mediated by the MAPK/NF-κB signaling pathway in HEK293 cells. 2021 Annals of Translational Medicine. All rights reserved.

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