Abstract. Evidence was recently provided for the activation of extracellular signal-regulated kinase (ERK), the best characterized mitogen-activated protein kinase, as an intracellular convergence point for mitogenic stimuli in animal models of glomerulonephritis (GN). In this study, in vivo ERK activity was blocked, with a pharmacologic inhibitor (U0126) of the ERK-activating kinase, in rats with mesangioproliferative GN. After injection of the monoclonal anti-Thy1.1 antibody (OX-7), the rats were treated (days 3 to 6) with low (10 mg/kg body wt) or high (100 mg/kg body wt) doses of U0126 administered intraperitoneally twice daily. On day 6 after induction of the disease, whole cortical tissue and isolated glomeruli were examined by using kinase activity assays, Western blot analyses, and immunohistochemical assays. Treatment with U0126 significantly reduced glomerular stimulation of ERK in antiThy1 GN. In the high dose-treated group, this downregulation was accompanied by a reduction in the number of glomerular mitotic figures, back to healthy control levels, and significant decreases in the numbers of total (P Ͻ 0.05) and 5-bromo-2'-deoxyuridine-positive (P Ͻ 0.05) glomerular cells. Immunohistochemical double-staining of renal sections demonstrated that mesangial cells were the major glomerular targets of U0126 in anti-Thy1 GN. These observations point to ERK as a putative intracellular mediator of the proliferative response in GN and suggest that pharmacologic treatments that interfere with the activation of ERK may be of potential therapeutic interest.Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduce extracellular stimuli to intracellular responses (1). Extracellular signal-regulated kinases (ERK) were the first reported and are still the best described members of the group of MAP kinases. Two ERK isoforms have been described; ERK1 (or p44 MAP kinase) and ERK2 (or p42 MAP kinase) are serine/threonine kinases that regulate the expression of many genes via the phosphorylation of several transcription factors (1,2). The binding of extracellular stimuli to G protein-coupled receptors or protein tyrosine kinase receptors results in the formation of GTP-Ras, which induces the sequential activation of cytoplasmic protein kinases, leading to their phosphorylation and activation (1,2). MAP kinase/ERK kinase 1 (MEK1) and MEK2 are specific activators of ERK1 and ERK2. MEK are dual-specificity protein kinases that phosphorylate both threonine and tyrosine regulatory sites in ERK (3). Although an extensive body of data describes the pivotal role of this signaling pathway in the control of cellular proliferation in vitro (1,2), little is known regarding the roles of ERK1 and ERK2 in physiologic or pathophysiologic conditions or their activation in vivo. Other members of the rapidly growing group of MAP kinases include stress-activated protein kinases, p38 MAP kinases (␣, , ␥, and ␦), ERK3, and ERK5 (1,2,4,5). Compared with ERK1 an...