title: Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression.
abstract: Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Ojima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Sayaka
authors.initials: S
authors.lastname: Maeda
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nishino
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Kei
authors.initials: K
authors.lastname: Fukami
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000077270:Exenatide; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D017127:Glycation End Products, Advanced / Q000502:physiology; D006801:Humans; D006984:Hypertrophy / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011484:Protein-Arginine N-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D010455:Peptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D018027:Receptors, Glucagon; D011971:Receptors, Immunologic; D012097:Repressor Proteins; D014688:Venoms; C018524:N,N-dimethylarginine; D052216:Glucagon-Like Peptide 1; D001120:Arginine; D000077270:Exenatide; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases