title: Hyperglycemia-induced GLP-1R downregulation causes RPE cell apoptosis.
abstract: Glucagon-like peptide-1 receptor (GLP-1R) is closely associated with the onset of diabetes and its complications. However, its roles in diabetic retinopathy are unknown. Retinal pigment epithelial (RPE) cells are a crucial component of the outer blood-retina barrier and their death is related to the progression of diabetic retinopathy. Thus, we examined the pathophysiological role of GLP-1R in RPE cell apoptosis. We found that GLP-1R expression was lower in the isolated neuroretina and RPE cells of streptozotocin-treated rats than in vehicle-treated rats. High-glucose treatment also decreased GLP-1R expression in a human RPE cell line (ARPE-19 cells). GLP-1R was silenced in ARPE-19 cells, in order to elucidate the pathophysiological roles of GLP-1R. This increased intracellular reactive oxygen species (ROS) generation and activated p53-mediated Bax promoter and endoplasmic reticulum (ER) stress signaling. We also found that GLP-1R knockdown-mediated p53 expression was regulated by ER stress. Interestingly, antioxidant treatment and peroxiredoxin 1 (Prx1) overexpression attenuated GLP-1R knockdown-induced ER stress signaling and p53 expression. Finally, to confirm that GLP-1R activation has protective effects, ARPE-19 cells were treated with exendin-4, a synthetic GLP-1R agonist. This attenuated high-glucose-induced ROS generation, ER stress signaling, and p53 expression. Collectively, these results indicated that hyperglycemia decreases GLP-1R expression in RPE cells. Such a decrease generates intracellular ROS, which increases ER stress-mediated p53 expression, and subsequently causes apoptosis by increasing Bax promoter activity. Our data suggested that regulation of GLP-1R expression is a promising approach for the treatment of diabetic retinopathy.
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, 500-757, Republic of Korea.
authors.forename: Dong-Il
authors.initials: DI
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, 500-757, Republic of Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Park
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, 500-757, Republic of Korea.
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Metabolism and Functionality Research Group, R & D Division, World Institute of Kimchi, Gwangzu, 503-360, Republic of Korea.
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Lim
authors.affiliation: Metabolism and Functionality Research Group, R & D Division, World Institute of Kimchi, Gwangzu, 503-360, Republic of Korea. Electronic address: hjchoi@wikim.re.kr.
authors.forename: Hak-Jong
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, 500-757, Republic of Korea. Electronic address: parksh@chonnam.ac.kr.
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000077270:Exenatide; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018027:Receptors, Glucagon; D016159:Tumor Suppressor Protein p53; D014688:Venoms; D051028:bcl-2-Associated X Protein; D013311:Streptozocin; D000077270:Exenatide; D005947:Glucose
keywords: Diabetic retinopathy; Endoplasmic reticulum stress; Glucagon-like peptide-1 receptor; P53; Reactive oxygen species