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Inhibition of ER stress attenuates kidney injury and apoptosis induced by 3-MCPD via regulating mitochondrial fission/fusion and Ca2+ homeostasis
- Source :
- Cell Biology and Toxicology. 37:795-809
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- 3-Chloro-1, 2-propanediol (3-MCPD) is a food-borne toxic substance well-known for more than 40 years that is mainly associated with nephrotoxicity. A better understanding of 3-MCPD nephrotoxicity is required to devise efficacious strategies to counteract its toxicity. In the present work, the role of endoplasmic reticulum (ER) stress along with its underlying regulatory mechanism in 3-MCPD-mediated renal cytotoxicity was investigated in vivo and in vitro. Our data indicated that 3-MCPD-stimulated ER stress response evidenced by sustained activation of PERK-ATF4-p-CHOP and IRE1 branches in Sprague Dawley (SD) rats and human embryonic kidney (HEK293) cells. Moreover, ER stress-associated specific apoptotic initiator, caspase 12, was over-expressed. Blocking ER stress with its antagonist, 4-phenylbutyric acid (4-PBA), improved the morphology and function of kidney effectively. 4-PBA also increased cell viability, relieved mitochondrial vacuolation, and inhibited cell apoptosis through regulating caspase-dependent intrinsic apoptosis pathways. Furthermore, the enhanced expressions of two mitochondrial fission proteins, DRP1/p-DRP1 and FIS1, and the relocation of DRP1 on mitochondria subjected to 3-MPCD were reversed by 4-PBA, while the expression of the fusion protein, MFN2, was restored. Moreover, cellular Ca2+ overload, the over-expression of CaMKK2, and the loss of mitochondria-associated membranes (MAM) were also relieved after 4-PBA co-treatment. Collectively, our data emphasized that ER stress plays critical role in 3-MCPD-mediated mitochondrial dysfunction and subsequent apoptosis as well as blockage of ER stress ameliorated kidney injury through improving mitochondrial fission/fusion and Ca2+ homeostasis. These findings provide a novel insight into the regulatory role of ER stress in 3-MCPD-associated nephropathy and a potential therapeutic strategy. Graphical Headlights 1. 4-PBA inhibits ER stress mainly through regulating PERK-ATF4-CHOP and IRE1-XBP1s branches. 2. Inhibition of ER stress by 4-PBA mitigates ER associated and mitochondrial apoptosis 3. Inhibition of ER stress by 4-PBA helps maintaining calcium homeostasis and mitochondrial dynamic.
- Subjects :
- 0301 basic medicine
FIS1
Chemistry
Health, Toxicology and Mutagenesis
Endoplasmic reticulum
Intrinsic apoptosis
MFN2
Cell Biology
Mitochondrion
Toxicology
Cell biology
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Apoptosis
030220 oncology & carcinogenesis
Unfolded protein response
Mitochondrial fission
Subjects
Details
- ISSN :
- 15736822 and 07422091
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- Cell Biology and Toxicology
- Accession number :
- edsair.doi...........53fa296cc943105dfa4b482eff29afab