Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression

^*Department of Pathology, Harvard Medical School and Center for Blood Research, Institute for Biomedical Research, 200 Longwood Avenue, Boston MA 02115; Departments of ^§Molecular Biology, ^∥Pathology, ^‡‡Internal Medicine (Nephrology), and ^**Pediatrics, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148; and ^††Department of Pathology, Tufts University School of Veterinary Medicine, North Grafton, MA 01536

Contributed by Eric N. Olson, December 29, 2003

Abstract

The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na⁺/Cl^–-coupled betaine/γ-aminobutyric acid transporter, and the Na⁺/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function.

Footnotes

↵ §§ To whom correspondence may be addressed. E-mail: arao{at}cbr.med.harvard.edu or eolson{at}hamon.swmed.edu.
↵ † Present address: Center for Genomic Regulation, Parc de Recerca Biomedica de Barcelona, E-08003 Barcelona, Spain.
↵ ‡ C.L.-R. and C.L.A. contributed equally to this work.
↵ ¶ Present address: Max-Planck-Institut fuer Entwicklungsbiologie, Spemannstrasse 35/III, D-72026, Tuebingen, Germany.
Abbreviations: AQP, aquaporin; AR, aldose reductase; BGT1, Na⁺/Cl^–-coupled betaine/γ-aminobutyric acid transporter; En, embryonic day n; SMIT, Na⁺-dependent myo-inositol transporter; TauT, Na⁺ and Cl^–-dependent taurine transporter; Pn, postnatal day n.