Blockade of (pro) renin receptor has benefits in diabetic angiotensin II type-1a-receptor–deficient mice, suggesting the importance of (pro) renin receptor–mediated intracellular signals. To determine the mechanism whereby the human (pro) renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal–related protein kinase (ERK) in a dose-and time-dependent manner but did not influence activation of p38 or c-Jun NH 2-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro) renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro) renin receptor–mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.