Linagliptin blocks renal damage in type 1 diabetic rats by suppressing advanced glycation end products-receptor axis

Horm Metab Res. 2014 Sep;46(10):717-21. doi: 10.1055/s-0034-1371892. Epub 2014 Apr 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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