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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 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/gamma-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.

Pubmed ID: 14983020


  • López-Rodríguez C
  • Antos CL
  • Shelton JM
  • Richardson JA
  • Lin F
  • Novobrantseva TI
  • Bronson RT
  • Igarashi P
  • Rao A
  • Olson EN


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 24, 2004

Associated Grants


Mesh Terms

  • Animals
  • Atrophy
  • DNA-Binding Proteins
  • Exons
  • Gene Expression Regulation
  • In Situ Hybridization
  • Kidney
  • Kidney Diseases
  • Mice
  • Mice, Knockout
  • NFATC Transcription Factors
  • Transcription Factors
  • Transcription, Genetic