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J. Biol. Chem., Vol. 281, Issue 38, 28048-28057, September 22, 2006

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Cyclin I Protects Podocytes from Apoptosis^*

Siân V. Griffin¹², J. Paul Olivier¹, Jeffrey W. Pippin, James M. Roberts, and Stuart J. Shankland³

From the Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, Washington 98195 and the Fred Hutchinson Cancer Research Center, Basic Sciences Division, Seattle, Washington 98109

The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (–/–) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I –/– mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21^Cip1/Waf1 protects podocytes from certain apoptotic stimuli. In cultured cyclin I –/– podocytes, the level of p21^Cip1/Waf1 was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild-type cells. Enforced expression of p21^Cip1/Waf1 reversed the susceptibility of cyclin I –/– podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21^Cip1/Waf1.

Received for publication, December 15, 2006 , and in revised form, June 26, 2006.

^* This work was supported by National Institutes of Health Grants DK60525, DK56799, and DK51096 (to S. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Supported by the American Heart Association.

³ An established member of the American Heart Association. To whom correspondence should be addressed: Dept. of Medicine, Division of Nephrology, University of Washington School of Medicine, 1959 NE Pacific St., Box 356521, Seattle, WA 98195. Tel.: 206-543-2346; Fax: 206-685-8661; E-mail: stuartjs{at}u.washington.edu.

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