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
Open accessAbstract
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.
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GLP-1RA could hinder the development of asymmetric dimethylarginine through AGE-RAGE mediation by suppressing the expression of protein arginine methyltransferase-1 and inhibiting ROS production.
“GLP-1RA could hinder the development of asymmetric dimethylarginine through AGE-RAGE mediation by suppressing the expression of protein arginine methyltransferase-1 and inhibiting ROS production.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [46]
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- Authors
- Ojima, A., Ishibashi, Y., Matsui, T., Maeda, S., Nishino, Y., Takeuchi, M., Fukami, K., & Yamagishi, S.-I.
- Affiliations
- Kurume University (JP)
- Kanazawa Medical University (JP)
- Corresponding author
- Yamagishi, Sho-ichi
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 182
- Issue
- 1
- Pages
- 132-141
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2000258452
- Cited by
- 156
- References
- 49
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 5 · 2021: 10 · 2020: 9 · 2019: 8 · 2018: 13 · 2017: 16 · 2016: 18 · 2015: 14 · 2014: 15 · 2013: 14
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- GLP-1 receptor agonists, exendin-4, asymmetric dimethylarginine, advanced glycation end products, RAGE, PRMT1, diabetic nephropathy, reactive oxygen species, proximal tubular epithelial cells, streptozotocin-induced diabetes, nitric oxide synthase inhibition, renal inflammation, 8-hydroxy-2'-deoxyguanosine, albuminuria
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Receptor for Advanced Glycation End Products, Exenatide, Animals, Arginine, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Drug Evaluation, Preclinical, Humans, Hypertrophy, Hypoglycemic Agents, Kidney, Kidney Glomerulus, Kidney Tubules, Macrophages, Male, Peptides, Protein-Arginine N-Methyltransferases, Receptors, Immunologic, Repressor Proteins, RNA, Messenger, Venoms, Gene Expression Regulation, Enzymologic, Glycation End Products, Advanced, Rats, Wistar, Reactive Oxygen Species, Receptors, Glucagon, Rats, Glucagon-Like Peptide 1
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