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.

• Authors: S Nakashima, T Matsui, M Takeuchi, S-I Yamagishi
• Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme (Horm Metab Res) Vol. 46 Issue 10 Pg. 717-21 (Sep 2014) ISSN: 1439-4286 [Electronic] Germany
• PMID: 24710699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Georg Thieme Verlag KG Stuttgart · New York.

Chemical References

• Glycation End Products, Advanced
• Purines
• Quinazolines
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic
• Intercellular Adhesion Molecule-1
• Linagliptin
• Dipeptidyl Peptidase 4

Topics

• Animals
• Diabetes Mellitus, Type 1 (complications)
• Diabetic Nephropathies (drug therapy, etiology, genetics, metabolism)
• Dipeptidyl Peptidase 4 (genetics)
• Glycation End Products, Advanced (metabolism)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Kidney (drug effects, metabolism)
• Linagliptin
• Male
• Purines (administration & dosage)
• Quinazolines (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic (genetics, metabolism)