4.5 Article

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

Journal

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 21, Issue 9, Pages 1967-1978

Publisher

WILEY
DOI: 10.1111/jcmm.13117

Keywords

PHD2; HIF; Endothelium; renal fibrosis; Pericyte coverage

Funding

  1. NIH [2R01HL102042-05]
  2. University of Mississippi Medical Center Intramural Research Support Program

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Accumulating evidence demonstrates that hypoxia-inducible factor (HIF-) hydroxylase system has a critical role in vascular remodelling. Using an endothelial-specific prolyl hydroxylase domain protein-2 (PHD2) knockout (PHD2(EC)KO) mouse model, this study investigates the regulatory role of endothelial HIF- hydroxylase system in the development of renal fibrosis. Knockout of PHD2 in EC up-regulated the expression of HIF-1 and HIF-2, 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-1) 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-1. 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-1 signalling and excessive pericyte coverage.

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