Up-regulation of TGF-β via the activation of extracellular signal-regulated kinase 1 and 2 induced by prorenin in human renal mesangial cells

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 (ERK 1/2) in cultured human renal mesangial cells (HRMCs). HRMCs cultured in vitro were pretreated with an AT(1) and AT(2) 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-beta was measured by ELISA. The mRNA of TGF-beta 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 ERK 1/2 and increase p-ERK1/2 in a time- and dose-dependent manner. The protein levels of TGF-beta increased significantly with the stimulation of prorenin. PD98059 significantly decreased p-ERK1/2. and then downregulated TGF-beta. HRP did not inhibit either ERK 1/2 phosphorylation or the increase in TGF-beta. ERK1/2 phosphorylation induced by prorenin led to a marked increase in TGF-beta. The regulation of TGF-beta 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-beta in HRMCs.