NDT Advance Access originally published online on September 24, 2007
Nephrology Dialysis Transplantation 2007 22(12):3431-3441; doi:10.1093/ndt/gfm428
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The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis
1Division of Nephrology, Augusta-Hospital, Bochum, 2Medical Policlinic, Div. of Nephrology, University of Bonn, Germany, 3Division of Pediatrics, National Matsumoto Hospital, Matsumoto-shi, Nagano, Japan, 4Bristol-Myers Squibb Co., Lawrenceville, NJ, USA, 5Pharmaceutical Chemistry, University of Bonn, and 6Div. of Nephrology and Immunology, RWTH University of Aachen, Germany
Correspondence and offprint requests to: Tammo Ostendorf, Division of Nephrology, University Hospital Aachen, Pauwelsstr. 30, D-52057 Aachen, Germany. Email: Tostendorf{at}ukaachen.de
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Abstract |
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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 p27Kip1 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 p27KIP1 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
The first two authors contributed equally to this work.
Received for publication: 27.10.06
Accepted in revised form: 6. 6.07
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