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Updated: Feb 24, 2026
Isolation and Culture of Cells from the Nephrogenic Zone of the Embryonic Mouse Kidney
Published on: April 22, 2011
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development
Hanako Kobayashi1, Jiao Liu2, Andres A Urrutia3
1Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
Insights
Combined inactivation of PHD2 and PHD3 in developing kidneys causes renal failure by disrupting nephron formation. This highlights the critical role of hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells for normal kidney development.
Area of Science:
- Developmental biology
- Renal physiology
- Molecular medicine
Background:
- Embryonic hypoxia is linked to growth defects and organ abnormalities.
- Kidney hypoxia can lead to reduced nephron endowment, chronic kidney disease, and hypertension.
- Hypoxia-inducible factors (HIFs), regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases, are key to cellular adaptation to low oxygen.
Purpose of the Study:
- To investigate the role of interstitial cell PHDs in kidney development during nephrogenesis.
- To determine the necessity of PHD2 and PHD3 in renal interstitial cells for normal kidney formation.
- To elucidate the involvement of HIF signaling in PHD-mediated renal development.
Main Methods:
- Genetic manipulation in mice to inactivate PHD genes in FOXD1-expressing stromal cells during nephrogenesis.
- Analysis of kidney development, size, glomerular number, and nephron formation in mutant mice.
- Assessment of HIF-2 signaling and stromal HIF activation in PHD-deficient kidneys.
Main Results:
- Combined inactivation of stromal PHD2 and PHD3 led to renal failure, reduced kidney size, fewer glomeruli, and abnormal postnatal nephron formation.
- Individual inactivation of PHD1, PHD2, or PHD3 did not impair nephrogenesis.
- The observed nephrogenesis defect in PHD2/PHD3 double mutants was dependent on intact HIF-2 signaling and the degree of stromal HIF activation.
Conclusions:
- Stromal PHD2 and PHD3 are essential for normal kidney development.
- Hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for proper nephron formation.
- Targeting PHD-HIF pathways may offer therapeutic strategies for developmental kidney diseases.
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.
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