Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development
| Autor: | Andres A. Urrutia, Malini Rajan, Jiao Liu, Volker H. Haase, Olena Davidoff, Hanako Kobayashi, Mikhail Burmakin, Ken Ishii, Zubaida Saifudeen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Stromal cell Procollagen-Proline Dioxygenase Kidney development Nephron Biology Hydroxylation Kidney Article Interstitial cell Hypoxia-Inducible Factor-Proline Dioxygenases Mice 03 medical and health sciences 0302 clinical medicine Pregnancy Internal medicine Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Molecular Targeted Therapy Renal Insufficiency Enzyme Inhibitors Hypoxia Renal stem cell Anemia Forkhead Transcription Factors Organ Size Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Cell Hypoxia Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Clinical Trials Phase III as Topic Hypoxia-inducible factors Nephrology 030220 oncology & carcinogenesis Mutation Kidney Diseases Female Stromal Cells Kidney disease |
| Zdroj: | Kidney International. 92:1370-1383 |
| ISSN: | 0085-2538 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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