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Intracellular methylglyoxal induces oxidative damage to pancreatic beta cell line INS-1 cell through Ire1α-JNK and mitochondrial apoptotic pathway.
- Source :
-
Free radical research [Free Radic Res] 2017 Apr; Vol. 51 (4), pp. 337-350. Date of Electronic Publication: 2017 May 10. - Publication Year :
- 2017
-
Abstract
- An increased intracellular methylglyoxal (MGO) under hyperglycemia led to pancreatic beta cell death. However, its mechanism in which way with MGO induced beta cell death remains unknown. We investigated both high glucose and MGO treatment significantly inclined intracellular MGO concentration and inhibited cell viability in vitro. MGO treatment also triggered intracellular advanced glycation end products (AGEs) formation, declined mitochondrial membrane potential (MMP), increased oxidative stress and the expression of ER stress mediators Grp78/Bip and p-PERK; activated mitochondrial apoptotic pathway, which could mimic by Glo1 knockdown. Aminoguanidine (AG), a MGO scavenger, however, prevented AGEs formation and MGO-induced cell death by inhibiting oxidative stress and ER stress. Furthermore, both antioxidant N-acetylcysteine (NAC) and ER stress inhibitor 4-phenylbutyrate (4-PBA) could attenuate MGO-induced cell death through ameliorating ER stress. MGO treatment down-regulated Ire1α, a key ER stress mediator, increased JNK phosphorylation and activated mitochondrial apoptosis; down-regulated Bcl-2 expression which could be attenuated by the JNK inhibitor SP600125 and further inhibited cytochrome c leakage from mitochondria and blocked the conversion of pro caspase 3 into cleaved caspase 3, all these might contribute to the inhibition of INS-1 cell apoptosis. Ire1α down-regulation by Ire1α siRNAs mimicked MGO-induced cytotoxicity by activating the JNK phosphorylation and mitochondrial apoptotic pathway. In summary, we demonstrated that increased intracellular MGO induced cytotoxicity in INS-1 cells primarily by activating oxidative stress and further triggering mitochondrial apoptotic pathway, and ER stress-mediated Ire1α-JNK pathway. These findings may have implication on new mechanism of glucotoxicity-mediated pancreatic beta-cell dysfunction.
- Subjects :
- Animals
Cell Proliferation drug effects
Cell Survival drug effects
Cells, Cultured
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum metabolism
Glucose administration & dosage
Glucose metabolism
Glucose pharmacology
Insulin-Secreting Cells metabolism
Insulin-Secreting Cells pathology
Mitochondria pathology
Pyruvaldehyde administration & dosage
Rats
Apoptosis drug effects
Endoribonucleases metabolism
Insulin-Secreting Cells drug effects
Intracellular Space metabolism
JNK Mitogen-Activated Protein Kinases metabolism
Mitochondria drug effects
Multienzyme Complexes metabolism
Oxidative Stress drug effects
Protein Serine-Threonine Kinases metabolism
Pyruvaldehyde pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1029-2470
- Volume :
- 51
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Free radical research
- Publication Type :
- Academic Journal
- Accession number :
- 28488455
- Full Text :
- https://doi.org/10.1080/10715762.2017.1289376