Olmesartan blocks advanced glycation end products-induced vcam-1 gene expression in mesangial cells by restoring Angiotensin-converting enzyme 2 level

Horm Metab Res. 2014 Jun;46(6):379-83. doi: 10.1055/s-0033-1361114. Epub 2013 Dec 2.


Advanced glycation end products (AGEs) and their receptor (RAGE) system are involved in diabetic nephropathy. Angiotensin-converting enzyme 2 (ACE 2) plays a protective role against cardiovascular and renal injury by stimulating the production of angiotensin-(1-7) [Ang-(1-7)], an antagonist of angiotensin II (Ang II). However, effects of the AGEs-RAGE axis on ACE 2 expression in mesangial cells remain unknown. We examined here the role of ACE 2 in the AGEs-RAGE-induced mesangial cell damage and investigated whether olmesartan, one of the Ang II type 1 receptor blockers (ARB), prevented the deleterious effects of AGEs via restoration of ACE 2 and Ang-(1-7) level. AGEs significantly increased superoxide generation, upregulated RAGE mRNA level, and decreased ACE 2 gene expression and Ang-(1-7) production in mesangial cells, all of which were blocked by olmesartan, but not by a different type of ARB, azilsartan. An antioxidant, N-acetylcysteine or RAGE-antibodies also restored the decrease in ACE 2 mRNA level in AGEs-exposed mesangial cells. Moreover, olmesartan, but not azilsartan completely inhibited the AGEs-induced increase in vascular cell adhesion molecule-1 (VCAM-1) mRNA level in mesangial cells, which was abolished by the treatment with A-779, an antagonist of Ang-(1-7) receptor, Mas receptor. Our present study suggests that olmesartan could block the AGEs-induced VCAM-1 gene induction in mesangial cells by restoring the downregulated ACE 2 levels and subsequently stimulating the Ang-(1-7)-Mas receptor axis. Restoration of ACE 2 levels and blockade of renin-angiotensin system by olmesartan might be a promising strategy for the treatment of diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I
  • Angiotensin-Converting Enzyme 2
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • Imidazoles / pharmacology*
  • Mesangial Cells / drug effects
  • Mesangial Cells / enzymology
  • Mesangial Cells / metabolism*
  • Peptide Fragments
  • Peptidyl-Dipeptidase A / metabolism*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism
  • Superoxides / metabolism
  • Tetrazoles / pharmacology*
  • Vascular Cell Adhesion Molecule-1 / genetics*
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Glycation End Products, Advanced
  • Imidazoles
  • Peptide Fragments
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Tetrazoles
  • Vascular Cell Adhesion Molecule-1
  • Superoxides
  • olmesartan
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)