Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury

Pharmacol Res. 2012 Mar;65(3):297-302. doi: 10.1016/j.phrs.2011.11.001. Epub 2011 Nov 10.


Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-β mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Biphenyl Compounds / pharmacology*
  • Cattle
  • Cells, Cultured
  • Diabetic Nephropathies / drug therapy
  • Glycation End Products, Advanced / antagonists & inhibitors
  • Glycation End Products, Advanced / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Irbesartan
  • Kidney / cytology*
  • Metformin / pharmacology*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / metabolism*
  • Serum Albumin, Bovine / antagonists & inhibitors
  • Serum Albumin, Bovine / metabolism
  • Tetrazoles / pharmacology*


  • Angiotensin II Type 1 Receptor Blockers
  • Biphenyl Compounds
  • Glycation End Products, Advanced
  • Hypoglycemic Agents
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Tetrazoles
  • advanced glycation end products-bovine serum albumin
  • Serum Albumin, Bovine
  • Metformin
  • Irbesartan