Angiotensin II causes β-cell dysfunction through an ER stress-induced proinflammatory response

Chan, S. M.H., Lau, Y.-S., Miller, A. A. , Ku, J. M., Potocnik, S., Ye, J.-M., Woodman, O. L. and Herbert, T. P. (2017) Angiotensin II causes β-cell dysfunction through an ER stress-induced proinflammatory response. Endocrinology, 158(10), pp. 3162-3173. (doi: 10.1210/en.2016-1879) (PMID:28938442)

160885.pdf - Accepted Version



The metabolic syndrome is associated with an increase in the activation of the renin angiotensin system, whose inhibition reduces the incidence of new-onset diabetes. Importantly, angiotensin II (AngII), independently of its vasoconstrictor action, causes β-cell inflammation and dysfunction, which may be an early step in the development of type 2 diabetes. The aim of this study was to determine how AngII causes β-cell dysfunction. Islets of Langerhans were isolated from C57BL/6J mice that had been infused with AngII in the presence or absence of taurine-conjugated ursodeoxycholic acid (TUDCA) and effects on endoplasmic reticulum (ER) stress, inflammation, and β-cell function determined. The mechanism of action of AngII was further investigated using isolated murine islets and clonal β cells. We show that AngII triggers ER stress, an increase in the messenger RNA expression of proinflammatory cytokines, and promotes β-cell dysfunction in murine islets of Langerhans both in vivo and ex vivo. These effects were significantly attenuated by TUDCA, an inhibitor of ER stress. We also show that AngII-induced ER stress is required for the increased expression of proinflammatory cytokines and is caused by reactive oxygen species and IP3 receptor activation. These data reveal that the induction of ER stress is critical for AngII-induced β-cell dysfunction and indicates how therapies that promote ER homeostasis may be beneficial in the prevention of type 2 diabetes.

Item Type:Articles
Additional Information:This work was supported by the School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University. Y.-S.L. was supported by the Australian Endeavour Scholarships and Fellowships and Ministry of Higher Education High Impact Research Grant H-20001-00- E000055.
Glasgow Author(s) Enlighten ID:Miller, Dr Alyson
Authors: Chan, S. M.H., Lau, Y.-S., Miller, A. A., Ku, J. M., Potocnik, S., Ye, J.-M., Woodman, O. L., and Herbert, T. P.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Endocrinology
Publisher:Endocrine Society
ISSN (Online):1945-7170
Published Online:17 August 2017
Copyright Holders:Copyright © 2017 Endocrine Society
First Published:First published in Endocrinology 158(10):3162-3173
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record