The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis.
BACKGROUND
In vitro, the extracellular signal-regulated kinase (ERK) is an intracellular convergence point of multiple stimuli, which affect the cell cycle. However, the role of ERK in cell cycle regulation in vivo is unknown.


METHODS
To address this issue, ERK activity was blocked both in vitro in mesangial cells (MC) and in vivo in experimental glomerulonephritis (GN) by a pharmacological inhibitor (U0126) of the ERK-activating kinase.


RESULTS
In stimulated MC, inhibition of ERK reduced cyclin-dependent kinase 2 (CDK2) phosphorylation, CDK2 activity and cyclin E/A expression, whereas downregulation of CDK inhibitor p27(Kip1) expression was inhibited. In vivo, U0126 was given to rats in the acute phase of anti-Thy 1.1 GN. We previously showed that glomerular cell proliferation was reduced by 67% upon treatment with the inhibitor compared to nephritic controls. Now, we detected a significant increase in renal CDK2-activity/phosphorylation in the nephritic controls, that was significantly and dose-dependently reduced by ERK inhibition. CDK2 activation was accompanied by an increase in renal expression of cyclins E/A and the enhanced binding of these cyclins to CDK2 in the nephritic controls. These changes were blunted by U0126 treatment. Finally, we noted an increased expression and CDK2-binding of p27(KIP1) protein in the nephritic controls which was decreased in U0126 treated rats.


CONCLUSIONS
Our observations provide the first evidence that ERK is an intracellular regulator of renal CDK2 activity in vivo in a glomerulonephritis model.
Bokemeyer
Dirk
D
Division of Nephrology, Augusta-Hospital, Bochum, Germany.
Panek
Darius
D
Kitahara
Masashi
M
Trzaskos
James M
JM
Müller
Christa E
CE
Hockemeyer
Jörg
J
Kunter
Uta
U
Boor
Peter
P
Floege
Jürgen
J
Kramer
Herbert J
HJ
Ostendorf
Tammo
T
D000818:Animals; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D005921:Glomerulonephritis / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases