| First Author | Zhao Y | Year | 2020 |
| Journal | Am J Physiol Renal Physiol | Volume | 319 |
| Issue | 2 | Pages | F345-F357 |
| PubMed ID | 32715763 | Mgi Jnum | J:296776 |
| Mgi Id | MGI:6469798 | Doi | 10.1152/ajprenal.00032.2020 |
| Citation | Zhao Y, et al. (2020) Endothelial prolyl hydroxylase 2 is necessary for angiotensin II-mediated renal fibrosis and injury. Am J Physiol Renal Physiol 319(2):F345-F357 |
| abstractText | Angiotensin II (ANG II) is the key contributor to renal fibrosis and injury. The present study investigated the role of endothelium prolyl hydroxylase 2 (PHD2) in ANG II-mediated renal fibrosis and injury. In vitro, endothelial cells (ECs) were isolated from PHD2(f/f) control [wild-type (WT)] mice or PHD2 EC knockout (PHD2(EC)KO) mice. In vivo, WT and PHD2(EC)KO mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) for 28 days. Renal fibrosis, reactive oxygen species (ROS), and iron contents were measured. Knockout of PHD2 resulted in a significant increase in the expression of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha in ECs. Intriguingly, knockout of PHD2 significantly reduced expression of the ANG II type 1 receptor (AT1R) in ECs. WT mice infused with ANG II caused increases in renal fibrosis, ROS formation, and iron contents. ANG II treatment led to a downregulation of PHD1 expression and upregulation of HIF-1alpha and HIF-2alpha in the renal cortex and medulla. Knockout of PHD2 in EC blunted ANG II-induced downregulation of PHD1 expression. Furthermore, knockout of PHD2 in ECs attenuated ANG II-induced expression of HIF-1alpha, HIF-2alpha, transforming growth factor-beta1, p47(phox), gp91(phox), heme oxygenase-1, and ferroportin. This was accompanied by a significant suppression of renal fibrosis, ROS formation, and iron accumulation. In summary, knockout of endothelial PHD2 suppressed the expression of AT1R in ECs and blunted ANG II-induced downregulation of PHD1 and upregulation of HIF-alpha in the kidney. Our study, for the first time, demonstrates a necessary role of endothelial PHD2 in ANG II-mediated renal fibrosis and injury. |
