Hemin mitigates contrast-induced nephropathy by inhibiting ferroptosis via HO-1/Nrf2/GPX4 pathway
Hemin mitigates contrast-induced nephropathy by inhibiting ferroptosis via HO-1/Nrf2/GPX4 pathway
复制标题
DOI：
10.1111/1440-1681.13673
复制
发表时间：
2022-06-10
影响因子：
2.9
通讯作者：
Zeng, Min
中科院分区：
文献类型：
--
作者：
Gao, Zhao;Zhang, Ziyue;Zeng, Min
造影剂肾病(CIN)是注射造影剂后常见的并发症，但仍缺乏有效的药物治疗。据报道，血红素加氧酶-1(HO-1)在抗肾损伤中起重要作用。HO-1诱导剂、抗卟啉类药物氯化血红素可能对CIN有良好的治疗效果。本研究旨在探讨氯化血红素对人近端小管上皮细胞(HK-2)CIN模型的影响及其分子机制。为了模拟经皮冠状动脉介入治疗(PCI)患者的常见情况，用高脂饮食的糖尿病大鼠静脉注射碘普罗胺诱导CIN。我们发现，在碘普罗胺之前服用氯化血红素，可以通过增强抗氧化能力和减少氧化应激来缓解CIN。经碘普罗胺损伤的HK-2细胞活力下降，活性氧(ROS)升高，氯化高铁血红素也能抑制这一变化。氯化血红素的作用涉及铁下垂的关键分子谷胱甘肽过氧化物酶(Gpx4)，小干扰RNA(SiRNA)下调Gpx4的表达可逆转氯化血红素对HK-2细胞的作用。此外，氯化血红素对Gpx4的诱导涉及HO-1和核因子红系相关因子2(Nrf2)。HO-1或Nrf2抑制剂在一定程度上阻止了氯化血红素对Gpx4的影响，而Nrf2的过表达增加了Gpx4的表达。此外，铁下垂抑制剂Liproxstatin-1的干预也减轻了体内的CIN。因此，我们发现氯化血红素通过激活HO-1/Nrf2上调Gpx4来减轻CIN，抑制氧化应激和铁下垂。氯化血红素作为一种临床用药，对CIN的治疗有一定的指导意义，抗铁下垂是CIN潜在的治疗策略。
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.