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Updated: Mar 2, 2026
Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
Activation of Hypoxia Signaling in Stromal Progenitors Impairs Kidney Development
Katharina Gerl1, Dominik Steppan1, Michaela Fuchs1
1Institute of Physiology, University of Regensburg, Regensburg, Germany.
Abstract:
Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel-Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.
Insights
Intrauterine hypoxia impairs kidney development by affecting renal stroma. Chronic activation of hypoxia-inducible factors (HIFs) in stromal progenitors disrupts nephrogenesis, highlighting the importance of oxygenation for kidney formation.
Area of Science:
- Developmental Biology
- Nephrology
- Molecular Biology
Background:
- Intrauterine hypoxia can impede kidney development, but the underlying cellular and molecular mechanisms are not fully understood.
- Hypoxia-inducible transcription factors (HIFs) are implicated in these effects, with their impact varying based on the cell type involved in kidney formation.
Purpose of the Study:
- To investigate the impact of HIF activation within the developing renal stroma on nephrogenesis.
- To elucidate the role of the von Hippel-Lindau (VHL) protein and HIFs in renal stromal progenitor cells.
Main Methods:
- Conditional deletion of the VHL protein in FOXD1-lineage stromal progenitors to activate HIFs.
- Analysis of kidney development, maturation, cell differentiation, and erythropoietin expression in genetically modified mice.
- Investigated the effects of co-deleting VHL with HIF2A or HIF1A, and the isolated deletion of HIF2A or HIF1A in stromal cells.
Main Results:
- VHL deletion in renal stroma led to kidney maturation defects and early postnatal death, with impaired nephron formation and cell differentiation.
- Enhanced erythropoietin expression was observed in VHL-deleted kidneys.
- Co-deletion of VHL and HIF2A, but not HIF1A, resulted in normal kidney development and lifespan, albeit with anemia due to reduced erythropoietin.
Conclusions:
- Sufficient intrauterine oxygenation is crucial for normal renal stroma differentiation and overall kidney development.
- Chronic HIF2 activation in renal stromal progenitors negatively impacts kidney development.
- Normal stromal function is essential for proper tubular differentiation during kidney development.
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