In vivo identification of the mitogen-activated protein kinase cascade as a central pathogenic pathway in experimental mesangioproliferative glomerulonephritis.
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 anti-Thy1 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 < 0.05) and 5-bromo-2'-deoxyuridine-positive (P < 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.
Bokemeyer
Dirk
D
Medical Policlinic, Division of Nephrology, University of Bonn, Bonn, Germany. bokemeyer@uni-bonn.de
Panek
Darius
D
Kramer
Herbert J
HJ
Lindemann
Marion
M
Kitahara
Masashi
M
Boor
Peter
P
Kerjaschki
Dontscho
D
Trzaskos
James M
JM
Floege
Jürgen
J
Ostendorf
Tammo
T
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D005921:Glomerulonephritis / Q000188:drug therapy / Q000209:etiology*; D007518:Isoantibodies / Q000276:immunology; D007678:Kidney Glomerulus / Q000473:pathology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats
D002070:Butadienes; D007518:Isoantibodies; D009570:Nitriles; C113580:U 0126; C035678:anti-Thy antibody; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases