title: 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 (PHD2ECKO) 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.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Duke University School of Medicine, Durham, NC, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.|Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Tao
authors.affiliation: Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Qin-Hui
authors.initials: QH
authors.lastname: Tuo
authors.affiliation: Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Changqin
authors.initials: C
authors.lastname: Deng
authors.affiliation: Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Jian-Xiong
authors.initials: JX
authors.lastname: Chen
mesh_terms: D000818:Animals; D001158:Arteries / Q000473:pathology; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure; D005355:Fibrosis; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology; D018345:Mice, Knockout; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017384:Sequence Deletion; D066253:Vascular Remodeling
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: Endothelium; HIF; PHD2; Pericyte coverage; renal fibrosis