Hemin mitigates contrast‐induced nephropathy by inhibiting ferroptosis via HO‐1/Nrf2/GPX4 pathway

Abstract Contrast‐induced nephropathy (CIN) is a common complication with adverse outcome after iodinated‐contrast injection, yet still lacking effective medication. Heme oxygenase‐1 (HO‐1) has been reported to play an important role against renal injuries. Hemin, a HO‐1 inducer and anti‐porphyria medicine, may have a promising effect against CIN. In this study, we aim to investigate the effect of hemin on CIN model and the underlying molecular mechanisms in human proximal tubule epithelial cells (HK‐2). To mimic a common condition in percutaneous coronary intervention (PCI) patients, CIN was induced by intravenous iopromide in high‐fat fed diabetic rats. We found hemin, given right before iopromide, mitigated CIN with enhanced antioxidative capacity and reduced oxidative stress. HK‐2 cells insulted by iopromide demonstrated decreased cell vitality and rising reactive oxygen species (ROS), which could also be inhibited by hemin. The effects of hemin involved a key molecule in ferroptosis, glutathione peroxidase (GPX4), whose down‐expression by small interfering RNA (siRNA) reversed the effect of hemin on HK‐2 cells. Furthermore, hemin's induction of GPX4 involved HO‐1 and nuclear factor erythroid 2‐related factor 2 (Nrf2). Either HO‐1 or Nrf2 inhibitor prevented hemin's effect on GPX4 to a comparable extent, and over‐expression of Nrf2 increased GPX4 expression. Moreover, intervention of ferroptosis inhibitor liproxstatin‐1 also alleviated CIN in vivo. Therefore, we showed hemin mitigated CIN, inhibiting oxidative stress and ferroptosis, by upregulation of GPX4 via activation of HO‐1/Nrf2. Hemin, as a clinical medicine, has a translational significance in treating CIN, and anti‐ferroptosis is a potential therapeutic strategy for CIN.