Cristina López-Rodrı́guez1, Christopher L. Antos1,2, John M. Shelton1, James A. Richardson1, Fangming Lin1, Tatiana I. Novobrantseva1, Roderick T. Bronson1, Peter Igarashi1, Anjana Rao1, Eric N. Olson1
1Department 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
2Max Planck Institute for Developmental Biology
Tóm tắt
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.
