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Molecular and Cellular Biology, August 2002, p. 5753-5760, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5753-5760.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

TonEBP/NFAT5 Stimulates Transcription of HSP70 in Response to Hypertonicity

Seung Kyoon Woo, Sang Do Lee, Ki Young Na, Won Kun Park, and H. Moo Kwon*

Department of Medicine, Johns Hopkins University, Baltimore, Maryland

Received 20 February 2002/ Returned for modification 30 April 2002/ Accepted 15 May 2002

While hyperosmolality of the kidney medulla is essential for urinary concentration, it imposes a great deal of stress. Cells in the renal medulla adapt to the stress of hypertonicity (hyperosmotic salt) by accumulating organic osmolytes. Tonicity-responsive enhancer (TonE) binding protein (TonEBP) (or NFAT5) stimulates transcription of transporters and a synthetic enzyme for the cellular accumulation of organic osmolytes. We found that dominant-negative TonEBP reduced expression of HSP70 as well as the transporters and enzyme. Near the major histocompatibility complex class III locus, there are three HSP70 genes named HSP70-1, HSP70-2, and HSC70t. While HSP70-1 and HSP70-2 were heat inducible, only HSP70-2 was induced by hypertonicity. In the 5' flanking region of the HSP70-2 gene, there are three sites for TonEBP binding. In cells transfected with a reporter plasmid containing this region, expression of luciferase was markedly stimulated in response to hypertonicity. Coexpression of the dominant-negative TonEBP reduced the luciferase expression. Mutating all three sites in the reporter plasmid led to a complete loss of induction by hypertonicity. Thus, TonEBP rather than heat shock factor stimulates transcription of the HSP70-2 gene in response to hypertonicity. We conclude that TonEBP is a master regulator of the renal medulla for cellular protection against high osmolality via organic osmolytes and molecular chaperones.

* Corresponding author. Mailing address: 963 Ross Building, 720 Rutland Ave., Baltimore, MD 21205. Phone: (410) 614-0085. Fax: (410) 502-9508. E-mail: mkwon{at}jhmi.edu.

Molecular and Cellular Biology, August 2002, p. 5753-5760, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5753-5760.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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