Contribution of Oxidative Stress to HIF-1-Mediated Profibrotic Changes during the Kidney Damage

Figure 1

Contribution of oxidative stress to HIF-1-mediated profibrotic changes during the kidney damage. (1) Under normoxia, HIF-α can be hydroxylated by PHD. Hydroxylated HIF-α can combinate with ubiquitin and be degraded following the activation of VHL, (2) while, under stress conditions such as hypoxia or inflammation, the increased ROS can suppress the activity of PHD, which further inhibits the hydroxylation and hydrolysis of HIF-α. (3) Meanwhile, excessive ROS can activate NF/κB signaling and then promote the expression of HIF-α. (4) Stabilized HIF-α dimerizes with HIF-β and translocates into the nucleus, activating a targeting gene. HIF-1 can promote apoptosis and lead to the release of inflammatory mediators such as IL-1β and TNF-α, triggering inflammation, while inflammation can aggravate hypoxia and oxidative stress further. Besides, HIF-1 may promote EMT and ECM deposition to mediate profibrotic changes by activating various transcriptional regulators and fibrogenic factors. (5) HIF-1 accumulation can also significantly enhance TGF-β expression. TGF-β can upregulate gene expression of Nox4 NADPH oxidase or directly activate NADPH oxidase to generate ROS, which may form a vicious cycle to lead to renal fibrosis. (6) In addition, HIF-1 can also regulate the expression of various microRNAs such as miR217, miR23a, and miR-21, then affecting the generation of ROS and promoting the development of fibrosis via activating PI-3K signaling.