In this present study, we examined the role of Na+/H+ exchanger 1 (NHE1) in the cultured rat vascular smooth muscle cell (VSMC) proliferation induced by advanced glycation end products (AGEs). AGEs significantly increased the [H-3] thymidine incorporation of VSMC. Cariporide, an NHE1 inhibitor, dose-dependently attenuated the AGEs-induced increase in cell DNA synthesis. Thus the effect of AGEs on NHE1 activity was next examined. The cariporide-dependent intracellular pH (pH(i)) was significantly increased after 24 h exposure to AGEs (10 mu g/ml). The direct AGEs-induced NHE1 activation was measured by the Na+-dependent intracellular pH recovery from intracellular acidosis. AGEs can increase the NHE1 activity in a time- and concentration-dependent manner. Inhibition of either the receptor for AGEs (RAGE) by anti-RAGE or mitogen-activated protein kinases (MAPK) by PD98059 reversed the effect of AGEs on NHE1 activity. Reverse transcription (RT)-PCR analysis revealed that AGEs dose-dependently increased NHE1 mRNA at 24 h. These findings demonstrate NHE1 is required for in AGEs-induced proliferation of VSMC, and AGEs increase NHE1 activity via the MAPK pathway. (C) 2008 Elsevier Inc. All Fights reserved.