The alterations in glomerular cell biology induced by glycated albumin resemble those caused by high ambient glucose, but are operative in physiologic (5.5 mM) glucose concentration. Recently, high glucose has been shown to activate extracellular signal-related kinase (ERK) in mesangial cells, but whether the mitogen-activated protein kinase (MAPK) cascade participates in signal transduction triggered by glycated albumin is unknown. Using a specific inhibitor of MAPK/ERK kinase, we demonstrate for the first time that activation of ERK is required for the inhibition of cell growth and enhanced elaboration of extracellular matrix protein provoked by glycated albumin. These findings indicate that the MAPK/ERK pathway mediates biologic activities of this glycated protein.