Τίτλος:
Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Aims: Although endoplasmic reticulum (ER) stress is recognized as a major mechanism causing pancreatic dysfunction in diabetes, little is known on how aging modulates the process. Here, we compared the response with ER stress, viability, and insulin release from pancreatic islets of young (6 weeks) or aged (14 months) mice. Results: Islets from aged mice were more sensitive to ER stress than their younger counterparts; they exhibited more pronounced unfolded protein response (UPR) and caspase activation and displayed compromised insulin release after high-glucose stimulation. Genetic ablation of p21 sensitized the islets to ER stress, especially in the aged group, whereas CHOP ablation was protective for islets from both aged and younger animals. Ciclopirox (CPX), an iron chelator that stimulates p21 expression, protected islets from glucotoxicity and mice from diet-induced diabetes, especially in the aged group in a manner that was both p21 and CHOP dependent. Innovation: For the first time, the study shows that age-dependent susceptibility to diet-induced diabetes is associated with the activity of p21 and CHOP in pancreatic islets and that CPX protects islets from glucotoxicity and mice from diabetes in an age-dependent manner. Conclusions: Our results identify ER stress as an age-dependent modifier of islet survival and function by mechanisms implicating enhancement of CHOP activity and inhibition of the protective activity of p21. These findings suggest that interventions restoring the homeostatic activity of ER stress, by agents such as CPX, may be particularly beneficial for the management of diabetes in the elderly. Antioxid. Redox Signal. 27, 185-200. © 2017, Mary Ann Liebert, Inc.
Συγγραφείς:
Mihailidou, C.
Chatzistamou, I.
Papavassiliou, A.G.
Kiaris, H.
Περιοδικό:
Antioxidants and Redox Signaling
Εκδότης:
MARY ANN LIEBERT INC PUBL
Λέξεις-κλειδιά:
caspase; ciclopirox; growth arrest and DNA damage inducible protein 153; insulin; p21 activated kinase; Cdkn1a protein, mouse; cyclin dependent kinase inhibitor 1A; Ddit3 protein, mouse; growth arrest and DNA damage inducible protein 153; insulin, adult; aged; animal cell; animal experiment; Article; cell aging; cell function; cell survival; cell viability; cohort analysis; comparative study; controlled study; diabetes mellitus; disease predisposition; endoplasmic reticulum stress; enzyme activation; genotype; glucose intake; glucotoxicity; in vivo study; insulin blood level; insulin release; mouse; nonhuman; pancreas islet; priority journal; prophylaxis; protein function; reverse transcription polymerase chain reaction; unfolded protein response; young adult; aging; animal; cell culture; cell survival; chemically induced; cytology; disease model; endoplasmic reticulum stress; gene expression regulation; gene knockout; genetics; lipid diet; metabolism; non insulin dependent diabetes mellitus; pancreas islet, Aging; Animals; Cell Survival; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation; Gene Knockout Techniques; Insulin; Islets of Langerhans; Mice; Transcription Factor CHOP
DOI:
10.1089/ars.2016.6671
