Control of Ferroptosis and Acute Tubular Necrosis by Female Sex Hormones and Estrogen Derivatives

女性性激素和雌激素衍生物控制铁死亡和急性肾小管坏死

• 批准号: 522190184
• 负责人: Professor Dr. Andreas Linkermann
• 金额: --
• 依托单位: Bereich Nephrologie/Dialyse
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/522190184?language=en
• 关键词: Control; Ferroptosis; Acute; Tubular; Necrosis

It has been recognized for longer than 6 decades that female tissues are resistant to ischemia-reperfusion injury (IRI), but an underlying mechanism remains elusive. Research during the last ten years has provided accumulating evidence for ferroptosis to contribute to IRI of various organs. Here, we identify isolated kidney tubules to be partially resistant to ferroptosis, and our preliminary data further indicate cell death propagation during ferroptosis of isolated kidney tubules to be inhibited by female sex hormones, such as 17beta-estradiol and its metabolites. These observations led us to the central hypothesis that estradiol derivatives function as ferroptosis inhibitors in general. Here, we propose to investigate systematically and in detail i) the antiferroptotic potency of female sex hormones, ii) the associated changes in lipid and oxilipid profiles of kidney tubules and iii) the regeneration of peroxidzed estradiols by oxidoreductases such as ferroptosis suppressor protein 1 (FSP1) in cell free systems and in vivo. This unique experimental setup will allow us to conclude on the mechanisms of estradiol-mediated control of ferroptosis in acute tubular necrosis and acute kidney injury.

女性组织对缺血再灌注损伤（IRI）具有抵抗力，但其机制尚不清楚。过去十年的研究为铁下垂导致各种器官的IRI提供了越来越多的证据。在这里，我们确定了孤立的肾小管是部分耐ferroptosis，我们的初步数据进一步表明，在ferroptosis孤立的肾小管细胞死亡传播受到抑制的女性性激素，如17 β-雌二醇及其代谢产物。这些观察结果使我们的中心假设，雌二醇衍生物的功能作为铁凋亡抑制剂一般。在这里，我们建议系统和详细地调查i）女性性激素的抗铁凋亡效力，ii）肾小管脂质和oxilipid配置文件的相关变化和iii）氧化还原酶，如铁凋亡抑制蛋白1（FSP 1）在无细胞系统和体内的过氧化雌二醇的再生。这种独特的实验设置将使我们能够得出结论的机制，雌二醇介导的控制铁在急性肾小管坏死和急性肾损伤。