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The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis.
Authors:Dirk Bokemeyer  Darius Panek  Masashi Kitahara  James M Trzaskos  Christa E Müller  J?rg Hockemeyer  Uta Kunter  Peter Boor  Jürgen Floege  Herbert J Kramer  Tammo Ostendorf
Affiliation:Division of Nephrology, Augusta-Hospital, Bochum, Germany.
Abstract:
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.
Keywords:cell cycle   cyclin A   cyclin E   MAP kinase   mesangial cell   p27Kip1
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