血红素通过 HO-1/Nrf2/GPX4 通路抑制铁死亡来减轻造影剂诱导的肾病,Clinical and Experimental Pharmacology and Physiology

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血红素通过 HO-1/Nrf2/GPX4 通路抑制铁死亡来减轻造影剂诱导的肾病
Clinical and Experimental Pharmacology and Physiology ( IF 2.4 ) Pub Date : 2022-05-22 , DOI: 10.1111/1440-1681.13673
Zhao Gao ₁ , Ziyue Zhang ₂ , Daqian Gu ₃ , Yunqian Li ₁ , Kun Zhang ₁ , Xiaoli Dong ₄ , Lingli Liu ₅ , Jiye Zhang ₆ , Jimin Chen ₇ , Duozhi Wu ₁ , Min Zeng ₁

Affiliation

造影剂肾病（CIN）是碘造影剂注射后常见的并发症，但仍缺乏有效的药物治疗。据报道，血红素加氧酶-1 (HO-1) 对肾损伤起重要作用。血红素是一种 HO-1 诱导剂和抗卟啉症药物，可能对 CIN 有很好的疗效。在这项研究中，我们旨在研究血红素对 CIN 模型的影响以及人近端小管上皮细胞 (HK-2) 的潜在分子机制。为了模拟经皮冠状动脉介入治疗 (PCI) 患者的常见情况，在高脂喂养的糖尿病大鼠中静脉注射碘普罗胺可诱导 CIN。我们发现，在碘普罗胺之前给予血红素，通过增强抗氧化能力和减少氧化应激来减轻 CIN。碘普罗胺损伤的 HK-2 细胞表现出细胞活力降低和活性氧 (ROS) 升高，这也可以被血红素抑制。血红素的作用涉及铁死亡中的关键分子谷胱甘肽过氧化物酶 (GPX4)，其通过小干扰 RNA (siRNA) 的下调逆转了血红素对 HK-2 细胞的作用。此外，血红素对 GPX4 的诱导涉及 HO-1 和核因子红细胞 2 相关因子 2 (Nrf2)。HO-1 或 Nrf2 抑制剂在相当程度上阻止了血红素对 GPX4 的影响，并且 Nrf2 的过表达增加了 GPX4 的表达。此外，ferroptosis 抑制剂 liproxstatin-1 的干预也减轻了体内 CIN。因此，我们发现血红素通过激活 HO-1/Nrf2 上调 GPX4 来减轻 CIN，抑制氧化应激和铁死亡。赫敏，

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

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.

更新日期：2022-05-22

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