Hepatocyte nuclear factor 1 alpha controls renal expression of the Npt1-Npt4 anionic transporter locus.
Hepatocyte nuclear factor 1 alpha (HNF1alpha) is a transcription factor that is expressed in liver, pancreas, kidney and intestine. Mice lacking HNF1alpha are born normally but suffer from several defects including hyperphenylalaninemia, defective bile acid and cholesterol metabolism, an insulin secretion defect and renal Fanconi syndrome. The renal phenotype involves a defect in renal proximal tubule reabsorption, leading to polyuria, glucosuria, aminoaciduria and phosphaturia. We investigated the expression of genes encoding members of the sodium/phosphate cotransporter (Na(+)/Pi) family (namely Npt1, Npt2, Npt4 and Ram1). We show that Npt1 and Npt4 genes were expressed at reduced levels in the kidneys of HNF1alpha -/- mice, whereas the expression of Npt2, the major renal phosphate transporter, was not affected. Analysis of the Npt1 genomic sequence revealed the existence of several alternative promoters activated in liver and/or in kidney. All of these were down-regulated in the kidneys of HNF1alpha -/- animals. Several HNF1alpha binding sites (BS) play an important role in the transcriptional control of this locus, including low-affinity HNF1 BSs localised in a DNase I hypersensitivity site (HSS3). Transient transfection experiments confirmed that HNF1alpha directly transactivates the Npt1 promoter and that the HSS3 region contributes to this activation.
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002843:Chromatin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D002843:Chromatin; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D020033:Protein Isoforms; C493546:SLC17A1 protein, human; C493548:SLC17A2 protein, human; C493550:SLC17A3 protein, human; C493547:Slc17a1 protein, mouse; C493549:Slc17a2 protein, mouse; C493551:Slc17a3 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta