Linagliptin Blocks Renal Damage in Type 1 Diabetic Rats by Suppressing Advanced Glycation End Products-Receptor Axis
Abstract
Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4) suppresses the AGE-induced oxidative stress generation and intercellular adhesion molecule-1 (ICAM-1) gene expression in endothelial cells. However, whether linagliptin could have beneficial effects on experimental diabetic nephropathy in a glucose-lowering independent manner remains unknown. To address the issue, this study examined the effects of linagliptin on renal damage in streptozotocin-induced diabetic rats. Serum levels of DPP-4 were significantly elevated in diabetic rats compared with control rats. Although linagliptin treatment for 2 weeks did not improve hyperglycemia in diabetic rats, linagliptin significantly reduced AGEs levels, RAGE gene expression, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress in the kidney of diabetic rats. Furthermore, linagliptin significantly reduced albuminuria, renal ICAM-1 mRNA levels, and lymphocyte infiltration into the glomeruli of diabetic rats. Our present study suggests that linagliptin could exert beneficial effects on diabetic nephropathy partly by blocking the AGE-RAGE-evoked oxidative stress generation in the kidney of streptozotocin-induced diabetic rats. Inhibition of DPP-4 by linagliptin might be a promising strategy for the treatment of diabetic nephropathy.
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Administration of PKF275-055 (3 mg/kg/day) or linagliptin in STZ-induced diabetic rats inhibited macrophage infiltration, inflammatory molecules, and NF-κB activity in the glomeruli and significantly reduced glomerular leukocyte infiltration.
“Administration of the DPP-4 inhibitor, PKF275-055 (3 mg/kg/day), or linagliptin in STZ-induced diabetic rats inhibited macrophage infiltration, inflammatory molecules, and NF-κB activity in the glomeruli [105] and significantly reduced glomerular leukocyte infiltration [106].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [106]
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Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control
Lee, Y.-S., & Jun, H.-S. (2016) · Mediators of Inflammation · doi:10.1155/2016/3094642 · Cited by 503 · see citing works
“Administration of the DPP-4 inhibitor, PKF275-055 (3mg/kg/day), or linagliptin in STZ-induced diabetic rats inhibited macrophage infiltration, inflammatorymolecules, andNF-κB activity in the glomeruli [105] and significantly reduced glomerular leukocyte infiltration [106].”
BackgroundFishman, S. L., Sonmez, H., Basman, C., Singh, V., & Poretsky, L. (2018) · Molecular Medicine · doi:10.1186/s10020-018-0060-3 · Cited by 330 · see citing works
The Role of Advanced Glycation End Products in Diabetic Vascular Complications
Rhee, S. Y., & Kim, Y. S. (2018) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2017.0105 · Cited by 274 · see citing works
Cooper, M. E., Perkovic, V., McGill, J. B., Groop, P.-H., Wanner, C., Rosenstock, J., Hehnke, U., Woerle, H.-J., & von Eynatten, M. (2015) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2015.03.024 · Cited by 110 · see citing works
- Authors
- Nakashima, S., Matsui, T., Takeuchi, M., & Yamagishi, S.-I.
- Affiliations
- Kurume University (JP)
- Kanazawa Medical University (JP)
- Venue
- Hormone and Metabolic Research
- Publisher
- Georg Thieme Verlag KG
- Published
- 2014-04-07
- Volume
- 46
- Issue
- 10
- Pages
- 717-721
- ISSN
- 0018-5043 (ISSN-L)
- 1439-4286
- OpenAlex
- W1967458701
- Cited by
- 90
- References
- 0
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 13 · 2014: 4
- FWCI
- 8.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hormone and Metabolic Research (publishedVersion)
- PubMed (publishedVersion)
- 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 › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- linagliptin, diabetic nephropathy, advanced glycation end products, RAGE, DPP-4 inhibition, oxidative stress, 8-hydroxy-2'-deoxyguanosine, ICAM-1, albuminuria, lymphocyte infiltration, glomeruli, streptozotocin-induced diabetes, type 1 diabetes, kidney injury
- MeSH terms
- Receptor for Advanced Glycation End Products, Linagliptin, Animals, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Humans, Kidney, Male, Purines, Quinazolines, Receptors, Immunologic, Glycation End Products, Advanced, Rats, Sprague-Dawley, Intercellular Adhesion Molecule-1, Dipeptidyl Peptidase 4, Rats
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