Telmisartan, an angiotensin II type I receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chernoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-γ activation

Interaction between advanced glycation end-products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy pathogenesis. Pathophysiological crosstalk between the AGEs-RAGE system and angiotensin II (Ang II) is also involved in this disease. This study investigated the role of proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity on inhibition of monocyte chemoattractant protein (MCP-1) expression. Telmisartan, an Ang II type 1 receptor blocker, downregulated RAGE mRNA and inhibited superoxide generation and MCP-1 gene expression in mesangial cells; these processes were blocked by GW9662, a PPAR-gamma inhibitor. Candesartan, an Ang II type 1 receptor blocker, did not suppress AGEs-induced superoxide generation. Telmisartan and the antioxidant, N-acetylcysteine, completely inhibited AGEs-induced MCP-1 overproduction by mesangial cells. These results suggest that telmisartan inhibits AGEs-signalling to MCP-1 expression in mesangial cells by downregulating RAGE gene expression and subsequent oxidative stress generation via PPAR-gamma activation. This study has demonstrated a unique benefit of telmisartan in that it may function as an anti-inflammatory agent against AGEs via PPAR-gamma activation and may play a protective role in diabetic nephropathy.