Prorenin is thought to be an inactive precursor of renin. This study investigated whether human prorenin was capable of activating the (pro)renin receptors [(P)RRs], leading to the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cultured human renal mesangial cells (HRMCs). HRMCs cultured in vitro were pretreated with an AT1 and AT2 blocker prior to stimulation by prorenin, PD98059 (an inhibitor of ERK1/2) and handle-region peptide (HRP). Phosphorylated ERK1/2 was evaluated using Western blot analysis, and the concentration of TGF-β was measured by ELISA. The mRNA of TGF-β was evaluated by RT-PCR. It was found that prorenin activated the (P)RR in cultured HRMCs, which in turn increased p-ERK1/2. Prorenin induced rapid phosphorylation of ERK1/2 and increased p-ERK1/2 in a time- and dose-dependent manner. The protein levels of TGF-β increased significantly with the stimulation of prorenin. PD98059 significantly decreased p-ERK1/2 and then downregulated TGF-β. HRP did not inhibit either ERK1/2 phosphorylation or the increase in TGF-β. ERK1/2 phosphorylation induced by prorenin led to a marked increase in TGF-β. The regulation of TGF-β was highly dependent on ERK1/2. Thus, ERK1/2 may play a key role in the development of kidney disease. HRP neither affects the ERK1/2 signaling nor the level of TGF-β in HRMCs.