Blockade of ERK1/2 by U0126 alleviates uric acid induced EMT and tubular cell injury in the rats with hyperuricemic nephropathy.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are serine/threonine kinases and function as regulators of cellular proliferation and differentiation. Recently, we demonstrated that inhibition of ERK1/2 alleviates the development and progression of hyperuricemia nephropathy (HN). However, its potential roles in uric acid-induced tubular epithelial-mesenchymal transition (EMT) and tubular epithelial cell injury are unknown. In this study, we showed that hyperuricemic injury induced EMT as characterized by down-regulation of E-cadherin and up-regulation of Vimentin and Snail1 in a rat model of HN. This was coincident with epithelial cells arrested at the G2/M phase of cell cycle, activation of Notch1/Jagged-1 and Wnt/β-catenin signaling pathways, and upregulation of matrix metalloproteinases 2 (MMP2) and MMP9. Administration of U0126, a selective inhibitor of ERK1/2, blocked all these responses. U0126 was also effective in inhibiting renal tubular cell injury as shown by decreased expression of lipocalin-2 (Lcn2) and kidney injury molecule-1 (Kim-1) and active forms of caspase-3. U0126 or ERK1/2 siRNA can inhibit tubular cell EMT and cell apoptosis as characterized with decreased expression of cleaved caspase-3. Moreover, ERK1/2 inhibition suppressed hyperuricemic injury-induced oxidative stress as indicated by decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD). Collectively, ERK1/2 inhibition-elicited renal protection is associated with inhibition of EMT through inactivation of multiple signaling pathways and matrix metalloproteinases, as well as attenuation of renal tubule injury by enhancing cellular resistance to oxidative stress.