Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodelling and fibrosis in mice.

Abstract

Accumulating evidence demonstrates that hypoxia-inducible factor (HIF-α) hydroxylase system has a critical role in vascular remodelling. Using an endothelial-specific prolyl hydroxylase domain protein-2 (PHD2) knockout (PHD2EC KO) mouse model, this study investigates the regulatory role of endothelial HIF-α hydroxylase system in the development of renal fibrosis. Knockout of PHD2 in EC up-regulated the expression of HIF-1α and HIF-2α, resulting in a significant decline of renal function as evidenced by elevated levels of serum creatinine. Deletion of PHD2 increased the expression of Notch3 and transforming growth factor (TGF-β1) in EC, thus further causing glomerular arteriolar remodelling with an increased pericyte and pericyte coverage. This was accompanied by a significant elevation of renal resistive index (RI). Moreover, knockout of PHD2 in EC up-regulated the expression of fibroblast-specific protein-1 (FSP-1) and increased interstitial fibrosis in the kidney. These alterations were strongly associated with up-regulation of Notch3 and TGF-β1. We concluded that the expression of PHD2 in endothelial cells plays a critical role in renal fibrosis and vascular remodelling in adult mice. Furthermore, these changes were strongly associated with up-regulation of Notch3/TGF-β1 signalling and excessive pericyte coverage.

• Authors: Shuo Wang, Heng Zeng, Sean T Chen, Liying Zhou, Xue-Jiao Xie, Xiaochen He, Yong-Kang Tao, Qin-Hui Tuo, Changqin Deng, Duan-Fang Liao, Jian-Xiong Chen
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 9 Pg. 1967-1978 (09 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28266128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Egln1 protein, mouse
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Animals
• Arteries (pathology)
• Arterioles (pathology)
• Blood Pressure
• Fibrosis
• Gene Expression Regulation
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (metabolism)
• Kidney (blood supply, pathology, physiopathology)
• Kidney Glomerulus (pathology, physiopathology)
• Mice, Knockout
• Pericytes (metabolism, pathology)
• Phenotype
• Sequence Deletion
• Vascular Remodeling