title: Overexpression of angiotensin II type 2 receptor promotes apoptosis and impairs insulin secretion in rat insulinoma cells.
abstract: Angiotensin II (Ang II), the major effector hormone of renin-angiotensin system, acts as a promoter of insulin resistance and diabetes mellitus type 2 pathogenesis. Activation of Ang II type 2 receptor (AT2R) has been examined as a potential therapeutic strategy. However, there are conflicting findings regarding the role of AT2R. In the current study, we evaluated the effects of overexpressing AT2R by viral vector transduction on the apoptosis and function of pancreatic β-islet cells. The rat insulinoma cell line, INS-1, was transduced with a recombinant adenoviral vector expressing AT2R (Ad-G-AT2R-EGFP). AT2R overexpression resulted in significantly reduced cell viability and subsequently impaired glucose-stimulated insulin secretion (GSIS) function in INS-1 cells. Down-regulated expressions of GSIS pathway components, insulin, glucose transporter 2, and glucokinase were associated with AT2R overexpression. Further analysis determined that overexpression of AT2R induced G1-phase cell cycle arrest and Ang II-independent apoptotic cell death as indicated by increased Annexin V staining. To understand the apoptosis signaling triggered by AT2R overexpression, levels of caspase proteins were measured. Overexpression of AT2R significantly induced caspase-8, caspase-9, and caspase-3 cleavage, and decreased Bcl-2, pAkt, and pERK expression levels. AT2R-induced cell apoptosis was successfully blocked by the caspase inhibitor Z-VAD-FMK. Our findings suggested that AT2R overexpression triggers the apoptosis of INS-1 cells and dysfunction in insulin secretion. In conclusion, more careful design and consideration are required when applying AT2R-related therapies in treating diabetes.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chinese People's Liberation Army General Hospital, No. 51, Road Fucheng, District Haidian, Beijing, 100048, China, liu_min8016@aliyun.com.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Danqing
authors.initials: D
authors.lastname: Jing
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Shinan
authors.initials: S
authors.lastname: Yin
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma / Q000235:genetics* / Q000473:pathology; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D007328:Insulin; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II