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Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
- Source :
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Kidney international [Kidney Int] 2017 Dec; Vol. 92 (6), pp. 1370-1383. Date of Electronic Publication: 2017 Aug 26. - Publication Year :
- 2017
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Abstract
- Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.<br /> (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Anemia blood
Anemia drug therapy
Anemia etiology
Animals
Cell Hypoxia physiology
Clinical Trials, Phase III as Topic
Disease Models, Animal
Enzyme Inhibitors therapeutic use
Forkhead Transcription Factors genetics
Forkhead Transcription Factors metabolism
Humans
Hydroxylation physiology
Hypoxia-Inducible Factor-Proline Dioxygenases antagonists & inhibitors
Hypoxia-Inducible Factor-Proline Dioxygenases genetics
Kidney cytology
Kidney metabolism
Kidney Diseases complications
Kidney Diseases drug therapy
Mice
Molecular Targeted Therapy methods
Mutation
Organ Size physiology
Procollagen-Proline Dioxygenase antagonists & inhibitors
Procollagen-Proline Dioxygenase genetics
Renal Insufficiency mortality
Renal Insufficiency pathology
Stromal Cells metabolism
Basic Helix-Loop-Helix Transcription Factors metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases physiology
Kidney growth & development
Procollagen-Proline Dioxygenase physiology
Renal Insufficiency genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1755
- Volume :
- 92
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Kidney international
- Publication Type :
- Academic Journal
- Accession number :
- 28847650
- Full Text :
- https://doi.org/10.1016/j.kint.2017.06.015