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

Am J Pathol. 2013 Jan;182(1):132-41. doi: 10.1016/j.ajpath.2012.09.016. Epub 2012 Nov 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / analogs & derivatives*
  • Arginine / biosynthesis
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Drug Evaluation, Preclinical / methods
  • Exenatide
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Glycation End Products, Advanced / physiology
  • Humans
  • Hypertrophy / prevention & control
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Kidney / metabolism*
  • Kidney Glomerulus / pathology
  • Kidney Tubules / metabolism
  • Macrophages / pathology
  • Male
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Protein-Arginine N-Methyltransferases / biosynthesis*
  • Protein-Arginine N-Methyltransferases / genetics
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Receptor for Advanced Glycation End Products
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / metabolism
  • Receptors, Immunologic / metabolism
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Venoms / pharmacology*
  • Venoms / therapeutic use


  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Glycation End Products, Advanced
  • Hypoglycemic Agents
  • Peptides
  • RNA, Messenger
  • Reactive Oxygen Species
  • Receptor for Advanced Glycation End Products
  • Receptors, Glucagon
  • Receptors, Immunologic
  • Repressor Proteins
  • Venoms
  • N,N-dimethylarginine
  • Glucagon-Like Peptide 1
  • Arginine
  • Exenatide
  • PRMT1 protein, human
  • Protein-Arginine N-Methyltransferases