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J. Biol. Chem., Vol. 283, Issue 36, 25082-25090, September 5, 2008

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Nucleoporin 88 (Nup88) Is Regulated by Hypertonic Stress in Kidney Cells to Retain the Transcription Factor Tonicity Enhancer-binding Protein (TonEBP) in the Nucleus^*

From the Division of Renal Diseases and Hypertension, School of Medicine, University Colorado Health Sciences Center, Denver, Colorado 80262

Antibody microarray technology identified Nup88 (nucleoporin 88) as a highly up-regulated protein in response to osmotic stress in inner medullary collecting duct (IMCD3) cells. Changes in expression were verified by Western blot and quantitative PCR for protein and message expression. In mouse and human kidney, Nup88 expression was substantial in the papilla, whereas it was nearly absent in the cortex. Furthermore, the expression of Nup88 increased 410.4 ± 22% in the papilla of mice after 36 h of thirsting. Nup88 protein expression in IMCD3 cells was significantly up-regulated in the first 8 h following exposure to acute osmotic stress, indicating that Nup88 is an early response protein. To define the function of Nup88 in the osmotic stress response, the transcription factor associated with hypertonicity, tonicity enhancer-binding protein (TonEBP), was cloned upstream of the green fluorescent protein. Employing this construct, we demonstrate that silencing Nup88 in IMCD3 cells acutely stressed to hypertonic conditions reduces nuclear retention of TonEBP, resulting in a substantial blunting in transcription of important osmotic stress response target genes and reduced cell viability. Finally, we show that in IMCD3 cells, nuclear export of TonEBP under isotonic conditions involves CRM-1 but under hypertonic stress is CRM1-independent. Our data, therefore, suggest that Nup88 is up-regulated in response to hypertonic stress and acts to retain TonEBP in the nucleus, activating transcription of critical osmoprotective genes.

Received for publication, March 27, 2008 , and in revised form, July 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK-19928 and DK-66544 (to T. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1-3 and Figs. 1 and 2.

¹ To whom correspondence should be addressed: University of Colorado Health Sciences Center, Division of Renal Diseases and Hypertension, School of Medicine, 4200 E. 9th Ave., Denver, CO 80262. Tel.: 303-315-7204; Fax: 303-315-4852; E-mail: tomas.berl{at}uchsc.edu.

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