Journal article
Hepatocyte Nuclear Factor-1 β Regulates Urinary Concentration and Response to Hypertonicity
Journal of the American Society of Nephrology, Vol.28(10), pp.2887-2900
10/2017
DOI: 10.1681/ASN.2016101095
PMCID: PMC5619957
PMID: 28507058
Abstract
The transcription factor hepatocyte nuclear factor-1
(HNF-1
) is essential for normal kidney development and function. Inactivation of HNF-1
in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1
specifically in renal collecting ducts (CDs). CD-specific HNF-1
mutant mice survived long term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, HNF-1
mutant mice exhibited polyuria and polydipsia. Before the development of significant renal structural abnormalities, mutant mice exhibited low urine osmolality at baseline and after water restriction and administration of desmopressin. However, mutant and wild-type mice had similar plasma vasopressin and solute excretion levels. HNF-1
mutant kidneys showed increased expression of aquaporin-2 mRNA but mislocalized expression of aquaporin-2 protein in the cytoplasm of CD cells. Mutant kidneys also had decreased expression of the UT-A urea transporter and collectrin, which is involved in apical membrane vesicle trafficking. Treatment of HNF-1
mutant mIMCD3 cells with hypertonic NaCl inhibited the induction of osmoregulated genes, including
, which encodes the transcription factor FXR that is required for maximal urinary concentration. Chromatin immunoprecipitation and sequencing experiments revealed HNF-1
binding to the
promoter in wild-type kidneys, and immunoblot analysis revealed downregulated expression of FXR in HNF-1
mutant kidneys. These findings reveal a novel role of HNF-1
in osmoregulation and identify multiple mechanisms, whereby mutations of HNF-1
produce defects in urinary concentration.
Details
- Title: Subtitle
- Hepatocyte Nuclear Factor-1 β Regulates Urinary Concentration and Response to Hypertonicity
- Creators
- Karam Aboudehen - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasLama Noureddine - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IowaPatricia Cobo-Stark - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasSvetlana Avdulov - Departments of Medicine andShayan Farahani - Departments of Medicine andMicah D Gearhart - Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MinnesotaDaniel G Bichet - Molecular and Integrative Physiology, Université de Montréal, Montreal, Quebec, Canada; andMarco Pontoglio - Department of Development, Reproduction and Cancer, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016/Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris-Descartes, Paris, FranceVishal Patel - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasPeter Igarashi - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.28(10), pp.2887-2900
- DOI
- 10.1681/ASN.2016101095
- PMID
- 28507058
- PMCID
- PMC5619957
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Grant note
- R01 DK102572 / NIDDK NIH HHS P30 DK079328 / NIDDK NIH HHS R37 DK042921 / NIDDK NIH HHS T32 DK007257 / NIDDK NIH HHS K08 DK084311 / NIDDK NIH HHS
- Language
- English
- Date published
- 10/2017
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094559002771
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