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

• Published in: Hormone and metabolic research Vol. 46; no. 6; p. 379
• Main Authors: Ishibashi, Y, Matsui, T, Yamagishi, S
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2014
• Subjects: Angiotensin I; 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
• ISSN: 1439-4286
• DOI: 10.1055/s-0033-1361114

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.