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Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor.
Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor.
- Source :
-
Journal of molecular endocrinology [J Mol Endocrinol] 2021 Aug 05; Vol. 67 (3), pp. 95-106. Date of Electronic Publication: 2021 Aug 05. - Publication Year :
- 2021
-
Abstract
- Long-term medication with dexamethasone - a synthetic glucocorticoid (GC) drug - results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed that dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TNSF10 (TRAIL) mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-κB, and Bax but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock-down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.
- Subjects :
- Animals
Biomarkers
Caspase 3 metabolism
Caspase 8 metabolism
Caspase Inhibitors pharmacology
Gene Knockdown Techniques
Male
Mice
NF-kappa B metabolism
Oxidative Stress
Proteolysis
Receptors, Glucocorticoid metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
Signal Transduction drug effects
TNF-Related Apoptosis-Inducing Ligand metabolism
Apoptosis drug effects
Dexamethasone pharmacology
Gene Expression Regulation
Receptors, TNF-Related Apoptosis-Inducing Ligand genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1479-6813
- Volume :
- 67
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of molecular endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 34223821
- Full Text :
- https://doi.org/10.1530/JME-20-0238