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J. Biol. Chem., Vol. 279, Issue 37, 39075-39084, September 10, 2004

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Gadd45 Proteins Induce G₂/M Arrest and Modulate Apoptosis in Kidney Cells Exposed to Hyperosmotic Stress^*

Sally K. Mak and Dietmar Kültz

From the Physiological Genomics Group, Department of Animal Sciences, University of California, Davis, California 95616

Gadd45 proteins are induced by hyperosmolality in renal inner medullary (IM) cells, but their role for cell adaptation to osmotic stress is not known. We show that a cell line derived from murine renal IM cells responds to moderate hyperosmotic stress (540 mosmol/kg) by activation of G₂/M arrest without significant apoptosis. If the severity of hyperosmotic stress exceeds the tolerance limit of this cell line (620 mosmol/kg) apoptosis is strongly induced. Using transient overexpression of ectopic Gadd45 proteins and simultaneous analysis of transfected versus non-transfected cells by laser-scanning cytometry, we were able to measure the effects of Gadd45 super-induction during hyperosmolality on G₂/M arrest and apoptosis. Our results demonstrate that induction of all three Gadd45 isoforms inhibits mitosis and promotes G₂/M arrest during moderate hyperosmotic stress but not in isosmotic controls. Furthermore, all three Gadd45 proteins are also involved in control of apoptosis during severe hyperosmotic stress. Under these conditions Gadd45 induction strongly potentiates apoptosis. In contrast, Gadd45/ induction transiently increases caspase 3/7 and annexin V binding before 12 h but inhibits later stages of apoptosis during severe hyperosmolality. These results show that Gadd45 isoforms function in common but also in distinct pathways during hyperosmolality and that their increased abundance contributes to the low mitotic index and protection of genomic integrity in cells of the mammalian renal inner medulla.

Received for publication, June 15, 2004 , and in revised form, July 13, 2004.

^* This work was supported by NIDDK, National Institutes of Health Grant DK59470 (to D. K.). 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.

To whom correspondence should be addressed: Physiological Genomics Group, Dept. of Animal Sciences, University of California, One Shields Ave., Meyer Hall, Davis, CA 95616. Tel.: 530-752-2991; Fax: 530-752-0175; E-mail: dkueltz{at}ucdavis.edu.

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