Loss of NFAT5 Results in Renal Atrophy and Lack of Tonicity-Responsive Gene Expression

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 viv...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 8; pp. 2392 - 2397
Main Authors López-Rodríguez, Cristina, Antos, Christopher L., Shelton, John M., Richardson, James A., Lin, Fangming, Novobrantseva, Tatiana I., Bronson, Roderick T., Igarashi, Peter, Rao, Anjana, Olson, Eric N.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 24.02.2004
National Acad Sciences
Subjects
Animal cells
Animals
Atrophy - genetics
Biological Sciences
Dehydration
DNA-Binding Proteins - deficiency
DNA-Binding Proteins - genetics
Epithelial cells
Exons
Fibroblasts
Gene Expression Regulation - genetics
Genes
Genetics
Histology
In Situ Hybridization
Kidney - abnormalities
Kidney - pathology
Kidney Diseases - genetics
Kidney Diseases - pathology
Kidney medulla
Kidneys
Membranes
Mice
Mice, Knockout
Mutation
NF-AT5 protein
NFAT5 protein
NFATC Transcription Factors
Stripes
T lymphocytes
Transcription Factors - deficiency
Transcription Factors - genetics
Transcription, Genetic
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Summary: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.
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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.
Contributed by Eric N. Olson, December 29, 2003
To whom correspondence may be addressed. E-mail: arao@cbr.med.harvard.edu or eolson@hamon.swmed.edu.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0308703100