期刊
KIDNEY INTERNATIONAL
卷 92, 期 6, 页码 1370-1383出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2017.06.015
关键词
chronic kidney disease; hypoxia; hypoxia-inducible factor; pericytes; prolyl-4-hydroxylase; renal development
资金
- Krick-Brooks chair in Nephrology, NIH [R01-DK101791, R01-DK081646]
- Department of Veterans Affairs Merit Award [1I01BX002348]
- NIDDK Diabetic Complications Consortium [U24-DK076169]
- Vanderbilt's Diabetes Research and Training Center [P30-DK20593]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据