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

Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2392-7. doi: 10.1073/pnas.0308703100.

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/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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Atrophy / genetics
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics*
  • Exons
  • Gene Expression Regulation / genetics*
  • In Situ Hybridization
  • Kidney / abnormalities*
  • Kidney / pathology
  • Kidney Diseases / genetics*
  • Kidney Diseases / pathology*
  • Mice
  • Mice, Knockout
  • NFATC Transcription Factors
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics*
  • Transcription, Genetic

Substances

  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • Transcription Factors