ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE IN PROLIFERATIVE GLOMERULONEPHRITIS IN RATS

Multiple extracellular mitogens are involved in the pathogenesis of pr oliferative forms of glomerulonephritis (GN), In vitro studies demonst rate the pivotal role of extracellular signal-regulated kinase (ERK) i n the regulation of cellular proliferation in response to extracellula r mitogens. In this study, we examined whether this kinase, as a conve rgence point of mitogenic stimuli, is activated in proliferative GN in vivo, Two different proliferative forms of anti-glomerular basal memb rane (GEM) GN in rats were induced and whole cortical tissue as well a s isolated glomeruli examined using kinase activity assays and Western blot analysis, Administration of rabbit anti-rat GEM serum to rats, p reimmunized with rabbit IgG, induced an accelerated crescentic anti-GE M GN. A significant increase in cortical, and more dramatically glomer ular ERK activity was detected at 1, 3, and 7 d after induction of GN, Immunization of Wistar-Kyoto rats with bovine GEM also induced a cres centic anti-GBM GN with an increase of renal cortical ERK activity aft er 4, 6, and 8 wk, ERK is phosphorylated and activated by the MAP kina se/ERK kinase (MEK), We detected a significant increase in the express ion of glomerular MEK in the accelerated form of anti-GEM CN, providin g a possible mechanism of long-term activation of ERK in this disease model, In contrast to ERK, activation of stress-activated protein kina se 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 prolif erative response to immune injury in GN and suggest that upregulation of MEK is involved in the long-term regulation of ERK in vivo.