The mitogen-activated protein kinase (MAPK) cascade plays an important role in the regulation of various cellular functions in glomerulonephritis (GN). Here, we investigated whether extracellular-signal regulated kinase 5 (ERK5)-a member of the MAPK family-is involved in the pathogenesis of chronic mesangioproliferative GN, using a rat model induced by uninephrectomy and anti-Thy-1 antibody injection. Immunostaining of kidneys obtained at different time points revealed that phospho-ERK5 was weakly expressed in control glomeruli, but dramatically increased in a typical mesangial pattern after 28 and 56 days of GN. A semiquantitative assessment indicated that glomerular phospho-ERK5 expression closely paralleled the accumulation of extracellular matrix (ECM), collagen type I, as well as glomerular expression of reactive oxygen species (ROS) and angiotensin II (Ang II). On the other hand, phospho-ERK1/2 expression increased on day 7 during the phase of enhanced mesangial cell proliferation and decreased thereafter. Each H₂O₂ and Ang II induced ERK5 phosphorylation by cultured rat mesangial cells (MCs). Co-stimulation with both H₂O₂ and Ang II synergistically increased MCs-ERK5 phosphorylation. Cultured MCs transfected with ERK5-specific siRNA showed a significant decrease in H₂O₂ or Ang II-induced cell viability and soluble collagen secretion compared with control cells. Treatment of GN rats with an Ang II type 1 receptor blocker resulted in significant decreases of phospho-ERK5 expression and collagen accumulation accompanied with a remarkable histological improvement. Taken together, these results suggest that MCs-ERK5 phosphorylation by Ang II or H₂O₂ enhances cell viability and ECM accumulation in an experimental model of chronic GN.