Hepatocyte nuclear factor 1 alpha controls renal expression of the Npt1-Npt4 anionic transporter locus

Claire Cheret; Antonia Doyen; Moshe Yaniv; Marco Pontoglio

doi:10.1016/s0022-2836(02)00816-1

Hepatocyte nuclear factor 1 alpha controls renal expression of the Npt1-Npt4 anionic transporter locus

J Mol Biol. 2002 Oct 4;322(5):929-41. doi: 10.1016/s0022-2836(02)00816-1.

Authors

Claire Cheret¹, Antonia Doyen, Moshe Yaniv, Marco Pontoglio

Affiliation

¹ Unité Expression Génétique et Maladies, Unité de Recherche Associée 1644 du Centre National de la Recherche Scientifique (CNRS), Département de Biologie du Développement, Institut Pasteur, Paris, France.

PMID: 12367519
DOI: 10.1016/s0022-2836(02)00816-1

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Binding Sites
Chromatin / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Exons / genetics
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 1-beta
Humans
Kidney / metabolism*
Liver / physiology
Mice
Molecular Sequence Data
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Promoter Regions, Genetic
Protein Isoforms / genetics
Protein Isoforms / metabolism
Sequence Alignment
Sodium-Phosphate Cotransporter Proteins
Sodium-Phosphate Cotransporter Proteins, Type I
Sodium-Phosphate Cotransporter Proteins, Type III
Symporters / genetics
Symporters / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic
Tumor Cells, Cultured

Substances

Chromatin
DNA-Binding Proteins
HNF1A protein, human
HNF1B protein, human
Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Hnf1b protein, mouse
Nuclear Proteins
Protein Isoforms
SLC17A1 protein, human
SLC17A2 protein, human
SLC17A3 protein, human
Slc17a1 protein, mouse
Slc17a2 protein, mouse
Slc17a3 protein, mouse
Sodium-Phosphate Cotransporter Proteins
Sodium-Phosphate Cotransporter Proteins, Type I
Sodium-Phosphate Cotransporter Proteins, Type III
Symporters
Transcription Factors
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-beta