Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development

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.

Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity

“…As a positive control we first analyzed erythropoietin ( Epo ) mRNA levels in liver and kidney tissue. In line with previous studies Epo and mRNA levels are markedly induced in Vhl −/− liver ( Figure 3 ) and kidney ( Figure 4 ) through HIF2α isoform [ 17 , 44 , 45 , 46 ]. We also found that the expression of Phd3 was induced consistently in the liver, kidney and lung of both Vhl −/− and Vhl −/− Hif1a −/− mice ( Figure 3 , Figure 4 and Figure 5 ), indicating that the induction of Phd3 in vivo was not driven by the HIF1α isoform in these three tissues ( Figure 3 , Figure 4 and Figure 5 ).…”

The Many Facets of Erythropoietin Physiologic and Metabolic Response

“…EPO binding to erythroid progenitor cells promotes their survival, proliferation, and differentiation to mature erythrocytes. EPO production is hypoxia inducible and is made in the interstitial cells in the adult kidney (Kobayashi et al, 2017;Anusornvongchai et al, 2018). In response to anemia, ischemic stress or high altitude, EPO production is induced (Pugh and Ratcliffe, 2017) and stimulates erythroid progenitor cells in the bone marrow to expand the erythroid lineage thus markedly increasing erythropoiesis and mature red blood cell production.…”

FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer

“…In addition, FOX transcription factors have been shown to associate with cancer research such as drug resistance, tumor growth, genomic alterations or drivers of initiation and thought to be a potential therapeutic strategy to combat cancer and putative biomarkers for specific cancers [ 6 , 10 ]. The FOXD subfamily includes FOXD1 , FOXD2 , FOXD3 and FOXD4 and functions as a critical regulator in normal cell development and disease progression [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Moreover, the FOXD subfamily has also been found to play a role as an important regulator for tumorigenesis and cancer progression [ 19 , 20 , 21 , 22 , 23 , 24 ], e.g., therapeutic resistance and cancer metastasis, and serves as a prognostic biomarker in several types of cancer [ 25 , 26 , 27 ].…”