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.
López-Rodríguez
Cristina
C
Department of Pathology, Harvard Medical School and Center for Blood Research, Institute for Biomedical Research, 200 Longwood Avenue, Boston MA 02115, USA.
Antos
Christopher L
CL
Shelton
John M
JM
Richardson
James A
JA
Lin
Fangming
F
Novobrantseva
Tatiana I
TI
Bronson
Roderick T
RT
Igarashi
Peter
P
Rao
Anjana
A
Olson
Eric N
EN
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