Telmisartan,an Angiotensin II Type 1 Receptor Blocker,Inhibits Advanced Glycation End-product (AGE)-induced Monocyte Chemoattractant Protein-1 Expression in Mesangial Cells through Downregulation of Receptor for AGEs via Peroxisome Proliferator-activated Receptor-γ Activation

Abstract

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-γ (PPAR-γ)-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-γ 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-γ activation. This study has demonstrated a unique benefit of telmisartan in that it may function as an anti-inflammatory agent against AGEs via PPAR-γ activation and may play a protective role in diabetic nephropathy.

Keywords

Telmisartan Candesartan GW9662 Advanced glycation end-products (AGEs)Diabetic nephropathy Peroxisome proliferator-activated receptor-γ (PPAR-γ) Oxidative stress Monocyte chemoattractant protein-1 (MCP-1)

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