Activation of extracellular signal-regulated kinase in proliferative glomerulonephritis in rats.

Abstract

Multiple extracellular mitogens are involved in the pathogenesis of proliferative forms of glomerulonephritis (GN). In vitro studies demonstrate the pivotal role of extracellular signal-regulated kinase (ERK) in the regulation of cellular proliferation in response to extracellular mitogens. In this study, we examined whether this kinase, as a convergence point of mitogenic stimuli, is activated in proliferative GN in vivo. Two different proliferative forms of anti-glomerular basal membrane (GBM) GN in rats were induced and whole cortical tissue as well as isolated glomeruli examined using kinase activity assays and Western blot analysis. Administration of rabbit anti-rat GBM serum to rats, preimmunized with rabbit IgG, induced an accelerated crescentic anti-GBM GN. A significant increase in cortical, and more dramatically glomerular ERK activity was detected at 1, 3, and 7 d after induction of GN. Immunization of WistarKyoto rats with bovine GBM also induced a crescentic anti-GBM GN with an increase of renal cortical ERK activity after 4, 6, and 8 wk. ERK is phosphorylated and activated by the MAP kinase/ERK kinase (MEK). We detected a significant increase in the expression of glomerular MEK in the accelerated form of anti-GBM GN, providing a possible mechanism of long-term activation of ERK in this disease model. In contrast to ERK, activation of stress-activated protein kinase was only detectable at early stages of proliferative GN, indicating these related kinases to serve distinct roles in the pathogenesis of GN. Our observations point to ERK as a putative mediator of the proliferative response to immune injury in GN and suggest that upregulation of MEK is involved in the long-term regulation of ERK in vivo. ( J. Clin. Invest. 1997. 100:582-588.)

Differential Contribution of Three Mitogen-Activated Protein Kinases to PDGF-BB-Induced Mesangial Cell Proliferation and Gene Expression

“…Particularly, the role of JNK is poorly understood, because of the lack of the specific inhibitor. We and other groups of investigators have reported that ERK, JNK, or p38 are activated in experimental glomerular diseases, such as hypertension (6,7), diabetes mellitus (DM) (8), and glomerulonephritis (9,10). Furthermore, we have also reported that activator protein-1 (AP-1), the transcriptional factor, is activated in various experimental glomerular diseases (6,7,11).…”

Effects of caveolin-1 and P-ERK1/2 on Ang II-induced glomerular mesangial cell proliferation

“…It acts by transmitting signals from the extracellular environment to be intracellular environment by activating tyrosine kinase receptor and G protein coupling receptors. 25,26 ERK1/2 has also been shown to be closely associated with many kidney diseases. In our study we showed that under control conditions only small amounts of p-ERK1/2 were located in the cytoplasm of GMCs, and that Ang II significantly increased p-ERK1/2 expression in cytoplasm and nuclei.…”

Regulation of MDR-1 (P-glycoprotein) by Cyclooxygenase-2

“…Western Blot Analysis-Western blot analysis was carried out as described previously (14). Cells were lysed in 50 mM HEPES, pH 7.5, containing 150 mM NaCl, 1.5 mM MgCl 2 , 1 mM EGTA, 10% glycerol, 1% Triton X-100, 1 g/ml aprotinin, 1 g/ml leupeptin, 1 mM phenylmethylsulfonyl fluoride, and 200 M orthovanadate.…”