Mesangial cells (MCs), vascular smooth muscle-derived cells, contribute to glomerular injury by generating a number of cytokines such as tumor necrosis factor-α (TNF-α). Matrix metalloproteinases (MMPs), regulated by various stimuli, are important in remodeling of glomerular ECM, which leads to a number of renal diseases. We investigated whether TNF-α participated in the regulation of MMPs and explored signal pathways involved in TNF-α-induced MMPs expression in rat glomerular MCs. Western blot and RT-qPCR results showed that treatment with TNF-α significantly increased the expression of MMP-2, but not MMP-9 at both protein and mRNA levels in rat glomerular MCs. The extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-κB) signal pathways were activated by TNF-α. Moreover, the activation of NF-κB pathway in rat MCs was effectively inhibited by PD98059, specific inhibitor of ERK, suggesting a role for ERK in regulating NF-κB function. PD98059 or NF-κB signal pathway selective inhibitor Bay 11-7082 effectively blocked TNF-α-induced expression of MMP-2 in rat MCs, as determined by gene and protein expression. C-jun N-terminal kinase (JNK) signal pathway had no effect on TNF-α-induced expression of MMP-2, even though it was also activated by TNF-α in rat MCs. Furthermore, TNF-α could induce the cell migration of rat MCs, whereas ERK signal pathway specific inhibitor PD98059 compromised the cell migration triggered by TNF-α. Thus, TNF-α upregulates the expression of MMP-2 via activation of ERK-dependent NF-κB pathway in rat MCs, which may contribute to the cell migration of rat MCs.