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Kidney Week

Abstract: SA-PO538

HIF Prolyl-4-Hydroxylation in FOXD1 Lineage Cells Is Essential for Normal Kidney Development

Session Information

  • Developmental Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Developmental Biology and Inherited Kidney Diseases

  • 401 Developmental Biology

Authors

  • Kobayashi, Hanako, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Haase, Volker H., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

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 (HIF) pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2 and PHD3. In the adult kidney, PHDs function as oxygen-sensors, are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. The role of interstitial cell PHDs in renal development, however, has not been examined.

Methods

In order to examine the role of interstitial HIF oxygen sensing in renal development and homeostasis, we used the Cre-loxP system to target all 3 HIF-PHDs in conjunction with HIF-1α or HIF-2α in FOXD1-expressing stromal cells.

Results

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 HIF-2 signaling and was dependent on the extent of stromal HIF activation.

Conclusion

The ability to regulate HIF prolyl-4-hydroxylation in FOXD1 stroma-derived cells is essential for normal nephron formation. Our data have implications for the therapeutic use of HIF prolyl-4-hydroxylase inhibitors, which are currently in phase 3 clinical development for renal anemia.

Funding

  • NIDDK Support