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J. Biol. Chem., Vol. 278, Issue 37, 35159-35167, September 12, 2003

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Mammalian Osmolytes and S-Nitrosoglutathione Promote F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein Maturation and Function^*

Marybeth Howard  , Horst Fischer ¶, Jeremie Roux ||, Bento C. Santos **, Steven R. Gullans , Paul H. Yancey  and William J. Welch  ¶¶

From the Department of Surgery and the ^||Department of Anesthesia, Surgical Research Laboratory, University of California, San Francisco, California 94110, the ^¶Children's Hospital Oakland Research Institute, Oakland, California 94609, the ^**Renal Division, Department of Medicine, Escola Paulista de Medicina, UNIFESP, 04023-900 Sao Paulo, Brazil, the Laboratory of Functional Genomics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, the Department of Biology, Whitman College, Walla Walla, Washington 99362, and the ^¶¶Department of Medicine and Physiology, University of California, San Francisco, California 94110

In cystic fibrosis, the absence of functional CFTR results in thick mucous secretions in the lung and intestines, as well as pancreatic deficiency. Although expressed at high levels in the kidney, mutations in CFTR result in little or no apparent kidney dysfunction. In an effort to understand this phenomenon, we analyzed F508 CFTR maturation and function in kidney cells under conditions that are common to the kidney, namely osmotic stress. Kidney cells were grown in culture and adapted to 250 mM NaCl and 250 mM urea. High performance liquid chromatography analysis of lysates from kidney cells adapted to these conditions identified an increase in the cellular osmolytes glycerophosphorylcholine, myo-inositol, sorbitol, and taurine. In contrast to isoosmotic conditions, hyperosmotic stress led to the proper folding and processing of F508 CFTR. Furthermore, three of the cellular osmolytes, when added individually to cells, proved effective in promoting the proper folding and processing of the F508 CFTR protein in both epithelial and fibroblast cells. Whole-cell patch clamping of osmolyte-treated cells showed that F508 CFTR had trafficked to the plasma membrane and was activated by forskolin. Encouraged by these findings, we looked at other features common to the kidney that may impact F508 maturation and function. Interestingly, a small molecule, S-nitrosoglutathione, which is a substrate for gamma glutamyltranspeptidase, an abundant enzyme in the kidney, likewise promoted F508 CFTR maturation and function. S-Nitrosoglutathione-corrected F508 CFTR exhibited a shorter half-life as compared with wild type CFTR. These results demonstrate the feasibility of a small molecule approach as a therapeutic treatment in promoting F508 CFTR maturation and function and suggest that an additional treatment may be required to stabilize F508 CFTR protein once present at the plasma membrane. Finally, our observations may help to explain why F508 homozygous patients do not present with kidney dysfunction.

Received for publication, February 24, 2003 , and in revised form, June 4, 2003.

^* This work was supported by National Institutes of Health Grants GM33551, DK51829, and 1P50HL60288, by the American Lung Association, and by the Cystic Fibrosis Research Institute. 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: Dept. of Surgery, University of California at San Francisco, 1001 Potrero Ave., Bldg. 1, Rm. 210, San Francisco, CA 94110. Tel.: 415-206-6884; Fax: 415-206-6997; E-mail: mbh1{at}itsa.ucsf.edu.

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