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Loss of NFAT5 Results in Renal Atrophy and Lack of Tonicity-Responsive Gene Expression

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Loss of NFAT5 Results in Renal Atrophy and Lack of Tonicity-Responsive Gene Expression Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression Cristina Lo´ pez-Rodrı´guez*†‡, Christopher L. Antos‡§¶, John M. Sheltonʈ, James A. Richardson§ʈ, Fangming Lin**, Tatiana I. Novobrantseva*, Roderick T. Bronson††, Peter Igarashi‡‡, Anjana Rao*§§, and Eric N. Olson§,§§ *Department of Pathology, Harvard Medical School and Center for Blood Research, Institute for Biomedical Research, 200 Longwood Avenue, Boston MA 02115; Departments of §Molecular Biology, ʈPathology, ‡‡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 Contributed by Eric N. Olson, December 29, 2003 The transcription factor NFAT5͞TonEBP, a member of the NFAT͞Rel and in other tissues, and several lines of evidence suggest its family of transcription factors, has been implicated in diverse involvement in the osmoprotective response (see ref. 10 for a cellular responses, including the response to osmotic stress, inte- review). NFAT5 binds tonicity-response elements that are grin-dependent cell migration, T cell activation, and the Ras path- present in the control regions of osmotically regulated genes, and way in Drosophila. To clarify the in vivo role of NFAT5, we it is hyperphosphorylated and translocates to the nucleus in generated NFAT5-null mice. Homozygous mutants were geneti- response to hypertonic stimulation of cells in culture (9–11). cally underrepresented after embryonic day 14.5. Surviving mice NFAT5 also undergoes nuclear translocation in the kidney manifested a progressive and profound atrophy of the kidney during antidiuresis, which is most apparent within the outer and medulla with impaired activation of several osmoprotective genes, inner regions of the medulla (12). -including those encoding aldose reductase, Na؉͞Cl؊-coupled be taine͞␥-aminobutyric acid transporter, and the Na؉͞myo-inositol In addition to its potential involvement in the osmotic stress cotransporter. The aldose reductase gene is controlled by a tonic- response, NFAT5 has been shown to be regulated by other ity-responsive enhancer, which was refractory to hypertonic stress stimuli and to participate in a diverse set of cellular responses. in fibroblasts lacking NFAT5, establishing this enhancer as a direct In response to T cell receptor stimulation, NFAT5 displays a ͞ transcriptional target of NFAT5. Our findings demonstrate a central dependence on the calcium calmodulin-dependent phosphatase role for NFAT5 as a tonicity-responsive transcription factor re- calcineurin (11, 13). On the other hand, the activation of NFAT5 quired for kidney homeostasis and function. by osmotic stress is independent of calcineurin (11). Intracellular signals transmitted by the prometastatic integrin ␣6͞␤4 also lead ecause water can diffuse freely across most membranes, to an increase in the levels and activity of NFAT5 that enhances Banimal cells must preserve a balanced osmolarity to prevent the migratory capacity of carcinoma cells (14). Finally, genetic dehydration and maintain viability. All nucleated cells possess a analyses in Drosophila suggest a role for dNFAT, the likely programmed response to hypertonic stress in which acute com- ortholog of mammalian NFAT5, in Ras-mediated cell pensatory changes in cell volume are followed by a coordinated growth (15). transcriptional response that results in the intracellular accumu- To define the functions of NFAT5 in the mouse, we disrupted lation of small, cell-compatible osmolytes, such as sorbitol, the mouse NFAT5 gene. The homozygous NFAT5 null allele myo-inositol, betaine, and taurine, which increase intracellular resulted in midembryonic lethality with incomplete penetrance. osmolality, restore cell volume, and provide a buffer against Surviving mutant mice displayed progressive growth retardation osmotic stress (1–3). The genes that are transcriptionally up- and perinatal lethality associated with severe renal abnormalities regulated during the osmoprotective response encode enzymes and impaired activation of osmoprotective genes, including AR. and membrane proteins involved in synthesis and transport of Cells lacking NFAT5 do not express AR mRNA because of their organic osmolytes. Among them, aldose reductase (AR) is inability to activate its tonicity-responsive enhancer. Our find- responsible for sorbitol synthesis, whereas the sodium- ͞␥ ings demonstrate a central role for NFAT5 as a tonicity- dependent myo-inositol cotransporter (SMIT), the betaine - responsive transcription factor required for renal homeostasis aminobutyric acid transporter (BGT1), and the sodium and and function. chloride-dependent taurine transporter (TauT) are membrane- ϩ localized cotransporters that rely on coupled influx of Na Materials and Methods and͞or ClϪ to mediate entry of osmolytes into osmotically Generation of a Targeted NFAT5 Allele. A 14-kb region surrounding stressed cells (1, 3). NFAT5 The cells in the kidney are specialized for water and ion the mouse gene was isolated from a genomic library. We retention and serve as the primary regulators of electrolyte constructed a mutant NFAT5-targeting vector by subcloning concentration in extracellular fluid (4). The rodent kidney 2.3-kb and 2.9-kb sequences surrounding the sixth exon, which medulla is regularly exposed to extreme hypertonic stress [up to encodes the DNA-binding loop of NFAT5. Gene targeting was 4,000 mOsm compared with 300 mOsm of serum (4), a hyper- tonicity required to concentrate urine and maintain serum Abbreviations: AQP, aquaporin; AR, aldose reductase; BGT1, Naϩ͞ClϪ-coupled betaine͞␥- osmolality constant under antidiuretic (hydropenic) conditions]. aminobutyric acid transporter; En, embryonic day n; SMIT, Naϩ-dependent myo-inositol An increase in extracellular osmolarity causes water to diffuse transporter; TauT, Naϩ and ClϪ-dependent taurine transporter; Pn, postnatal day n. out of the medullary cells, so they must counter this stress by †Present address: Center for Genomic Regulation, Parc de Recerca Biomedica de Barcelona, synthesizing and accumulating osmolytes. Diseases that impair E-08003 Barcelona, Spain. kidney functions lead to pathological imbalances in the tonicity ‡C.L.-R. and C.L.A. contributed equally to this work. of body fluids, which disturb other organ systems. ¶Present address: Max-Planck-Institut fuer Entwicklungsbiologie, Spemannstrasse 35͞III, NFAT5 (TonEBP and OREBP) is a member of the NFAT͞ D-72026, Tuebingen, Germany. Rel family of transcription factors (5, 6), which contains a §§To whom correspondence may be addressed. E-mail: [email protected] or DNA-binding domain related to both the NFAT and NF␬B [email protected]. families (5–9). NFAT5 is highly expressed in the kidney medulla © 2004 by The National Academy of Sciences of the USA 2392–2397 ͉ PNAS ͉ February 24, 2004 ͉ vol. 101 ͉ no. 8 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0308703100 Downloaded by guest on October 7, 2021 Fig. 1. Targeted disruption of the NFAT5 gene. (A) Strategy used to generate the targeted NFAT5 allele. The targeted locus substitutes an inverted Neo cassette for the sixth exon of the NFAT5 gene (first exon of the Rel-homology domain, which encodes the DNA-binding loop), generating a frameshift that introduces a stop codon immediately after the deletion (not shown). B, BamHI; P, PsthAI; A, AvrII; X, XmnI; Bg, BglII. (B) Southern blot analysis from BamHI-restricted genomic DNA with a 5Ј probe outside the recombination site identifies the targeted NFAT5 allele in heterozygous mouse crosses. (C) Western blot analysis for NFAT5 protein in lymphocytes from wild-type and NFAT5Ϫ/Ϫ mice shows complete lack of NFAT5 expression in the mutant. Protein levels of NFAT1 are unaffected in the homozygous mutant (Lower). ns, nonspecific band. performed as described in Supporting Text, which is published as Sixteen hours after stimulation, cells were harvested and lucif- supporting information on the PNAS web site. erase activity was assessed as described (5). Photinus luciferase values were normalized to an independent reporter (Renilla Histology and Immunostaining. Histology and terminal de- luciferase). All experiments were performed at least twice, and oxynucleotidyltransferase-mediated dUTP end-labeling analysis a representative experiment is shown in the figure. GENETICS were performed as described in Supporting Text. Formalin-fixed and paraffin-embedded kidney sections were incubated with Quantitative RT-PCR. RNA isolation and RT-PCR were per- rabbit primary antibodies to aquaporin 2 (AQP2, Mark Knepper, formed as described in Supporting Text. National Institutes of Health, see ref. 16) at 1:2,000 dilution or aquaporin 3 (AQP3, Santa Cruz Biotechnology) at 1:1,000 Results dilution at room temperature for 2 h, followed by further Generation of NFAT5؊/؊ Mice. We inactivated the mouse NFAT5 incubation with Alexa Fluor 488 anti-rabbit IgG (Vector Lab- gene by replacing the Rel-DNA binding domain within the sixth oratories) at 1:400 dilution at room temperature for 40 min. exon with an inverted neomycin-resistance cassette (Fig. 1A). Stained sections were photographed under epifluorescence il- Homologous recombination introduced an additional BamHI lumination by using a Zeiss Axioplan microscope, and the restriction site into the NFAT5 locus, generating 7.3- and 9.0-kb images were analyzed with OPENLAB software (Improvision, fragments instead of the 15.3-kb fragment
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