Activation of extracellular signal-regulated kinase in proliferative glomerulonephritis in rats.
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 Wistar-Kyoto 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.
Bokemeyer
D
D
Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Guglielmi
K E
KE
McGinty
A
A
Sorokin
A
A
Lianos
E A
EA
Dunn
M J
MJ
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002417:Cattle; D004789:Enzyme Activation; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D017871:Calcium-Calmodulin-Dependent Protein Kinases