Endothelial prolyl hydroxylase 2 is necessary for Angiotensin II‐mediated renal fibrosis and reactive oxygen species formation

Abstract

Angiotensin II (Ang‐II) is one of the major contributors to the progression of chronic kidney disease and renal fibrosis. The aim of present study is to investigate the role of endothelial oxygen sensor prolyl hydroxylase‐2 (PHD2) in the Ang‐II‐mediated renal fibrosis and reactive oxygen species (ROS) formation. Wild type (WT) mice and PHD2 endothelial cell‐specific knockout (PHD2ECKO) mice were infused with Ang‐II (1000ng/kg/min) for 28 days. Renal fibrosis, ROS formation, and iron contents were measured by Masson’s trichrome, dihydroethidium, and Prussian blue staining, respectively. In the WT mice, infusion with Ang‐II caused a significant increase in the fibrosis area of kidney. Ang‐II infusion also significantly increased the ROS formation and iron contents. Furthermore, the levels of hypoxia‐inducible factor (HIF)‐1α, HIF‐2α, transforming growth factor‐β1 (TGF‐β1), p47phox and gp91phox, heme oxygenase‐1 (HO‐1), ferroportin, caspase‐3, p53 and the acetylation of p53 (Acetyl‐p53) in both renal cortex and medulla were significantly upregulated after infusion with Ang‐II in WT mice. Interestingly, knockout of PHD2 in endothelium led to a significant suppression of Ang‐II‐induced renal fibrosis, ROS formation and iron accumulation. The expression of HIF‐1α, HIF‐2α, TGF‐β1, p47phox, gp91phox, HO‐1, ferroportin, caspase‐3, p53 and Acetyl‐p53 was also significantly reduced in the PHD2ECKO mice infused with Ang‐II compared with the WT mice infused with Ang‐II. Our study for the first time demonstrates that the endothelial PHD2 is necessary for Ang‐II‐mediated renal fibrosis and injury. Specific knockout of endothelial PHD2 protects the kidney against Ang‐II‐induced fibrosis and ROS formation.Support or Funding InformationThis work was supported by the National Institutes of Health grant 2R01HL102042‐7 and University of Mississippi Medical Center Intramural Research Support Program to J.X. Chen.