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.
Department of Pathology, Harvard Medical School and Center for Blood Research, Institute for Biomedical Research, 200 Longwood Avenue, Boston MA 02115, USA.
Cristina
C
López-Rodríguez
Christopher L
CL
Antos
John M
JM
Shelton
James A
JA
Richardson
Fangming
F
Lin
Tatiana I
TI
Novobrantseva
Roderick T
RT
Bronson
Peter
P
Igarashi
Anjana
A
Rao
Eric N
EN
Olson
D000818:Animals; D001284:Atrophy / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation / Q000235:genetics*; D017403:In Situ Hybridization; D007668:Kidney / Q000002:abnormalities* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D014157:Transcription Factors