Swainsonine Triggers Paraptosis via ER Stress and MAPK Signaling Pathway in Rat Primary Renal Tubular Epithelial Cells

Swainsonine (SW), an indolizidine alkaloid extracted from locoweeds, was shown toxic effects in multiple studies, but the underlying action mechanism remains unclear. SW is known to cause autophagy and apoptosis, but there has been no report on paraptosis mediated cell death. Here, we showed that SW...

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Published inFrontiers in pharmacology Vol. 12; p. 715285
Main Authors Wang, Shuai, Guo, Yazhou, Yang, Chen, Huang, Ruijie, Wen, Yuting, Zhang, Chunyan, Wu, Chenchen, Zhao, Baoyu
Format Journal Article
LanguageEnglish
Published Frontiers Media S.A 10.08.2021
Subjects
er stress
MAPK
paraptosis
Pharmacology
swainsonine
vacuolation
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Summary:Swainsonine (SW), an indolizidine alkaloid extracted from locoweeds, was shown toxic effects in multiple studies, but the underlying action mechanism remains unclear. SW is known to cause autophagy and apoptosis, but there has been no report on paraptosis mediated cell death. Here, we showed that SW induced rat primary renal tubular epithelial cells (RTECs) death accompanied by vacuolation in vitro . The fluorescence with the endoplasmic reticulum (ER)-Tracker Red and transmission electron microscopy (TEM) results indicated that the vacuoles were of ER origin, typical of paraptosis. The level of ER stress markers, such as polyubiquitinated proteins, Bip, CHOP and cytoplasmic concentration of Ca 2+ have drastically increased. Interestingly, autophagy inhibitor could not interrupt but enhanced the induction of cytoplasmic vacuolization. Furthermore, MAPK pathways were activated by SW and inhibitors of ERK and JNK pathways could prevent the formation of cytoplasmic vacuolization. In this study, we confirmed that SW induced cell paraptosis through ER stress and MAPK signaling pathway, thus further laying a theoretical foundation for the study of SW toxicity mechanism.
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This article was submitted to Predictive Toxicology, a section of the journal Frontiers in Pharmacology
Edited by:Yanzhu Zhu, Chinese Academy of Agricultural Sciences (CAAS), China
These authors have contributed equally to this work
Reviewed by:Jianhai Zhang, Shanxi Agricultural University, China
Lin Wang, Shandong Agricultural University, China
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2021.715285