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Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is
essential for normal kidney development.
Authors Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O,
Saifudeen Z, Haase VH
Submitted By Submitted Externally on 11/27/2017
Status Published
Journal Kidney international
Year 2017
Date Published 12/1/2017
Volume : Pages 92 : 1370 - 1383
PubMed Reference 28847650
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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