Novel redox mechanisms of oxygenated phospholipids in chronic and diabetic kidney disease

慢性和糖尿病肾病中含氧磷脂的新氧化还原机制

基本信息

项目摘要

Oxidative stress has long been implicated in the pathogenesis of diabetic and chronic kidney disease (DKD/CKD). Most of the previous studies focused on either a singular concept of oxidative stress vs antioxidant balance, or centered on overproduction of superoxide as a major reactive oxygen species (ROS) and a primary event in DKD/CKD. However, superoxide has major kinetic and biochemical barriers that limit its impacts on biological structures. We propose a key role for less reactive, more specific and membrane diffusible molecules which are also tightly related to changes in cell metabolism – (phospho)lipid peroxides (LOOH). While the basic tenets of lipid peroxidation are established in biology, the molecular entity, modes of action and specific redox signaling ability of LOOH are more enigmatic. This is a critical gap to address because impeding a highly specific form of redox signal at the right timing in disease pathogenesis can prevent renal cell dysfunction. Our central hypothesis is that LOOH are key metabolic signals that transmit an initial redox stress in cells. Furthermore, we propose that diabetes alters the molecular signature of LOOH and that from a myriad of diverse oxidized phospholipids, there are only a few specific ones that dictate the activation of programmed cell death. We focus on proximal tubular epithelial cells (PTC) which comprise ~ 70-80 % of the cortex, where we previously discovered that dysregulation of PTC metabolism potentiates LOOH production. We have a broad array of preliminary data showing that when PTC metabolism is challenged either by lipid overload or by ablating the neutralizing mechanism for membrane peroxides via deletion of glutathione peroxidase 4 (GPx4), LOOH are overproduced and mice develop kidney injury. Using diabetic models, we show that diabetes not only potentiates the formation of LOOH, but also alters the molecular signature of LOOH species in a fashion that oxidized phosphatidylethanolamines (PE) and lysophosphatidylethanolamine (LPE) become abundant. Three aims will test the hypothesis using state-of-the-art biophysical and mass spectrometry imaging methods in combination with pharmacologic and transgenic approaches using both established and newly generated mouse models. In Aim 1, we will test the prediction that changes in PTC metabolic activity regulates the production of LOOH. Aim 2 will explore mechanisms through which diabetes potentiates the production of specific oxygenated phospholipids. In Aim 3, we will test the hypothesis, that selective oxidation of phospholipid species dictates the activation of renal cell death programs. The experimental strategy combines PTC-specific transgenic models, obese CKD and diabetic DKD models, using targeted compounds to delinate originating sources of redox stress and advanced redox phospholipidomics and biophysical approaches. Outcomes from this proposal will establish a new, more specific view of redox stress in CKD/DKD and link specific oxidized (phospho)lipids to PTC injury and demise, paving the way to highly specific anti-apoptotic or anti-ferroptotic interventions in the future.
氧化应激长期以来一直与糖尿病和慢性肾脏疾病的发病机制有关。 (DKD/CKD)。以前的大多数研究都集中在氧化应激的单一概念与 抗氧化剂平衡,或以过量产生超氧化物为主要的活性氧物种(ROS) 在DKD/CKD中为主要事件。然而,超氧化物具有主要的动力学和生物化学障碍,限制了其 对生物结构的影响。我们提出了一个关键作用,即反应性较低,更具特异性和膜 与细胞代谢变化密切相关的可扩散分子--(磷)过氧化脂质 (呵呵)。虽然脂质过氧化的基本原理是在生物学中确立的,但其分子实体、模式 LOOH的作用和特定的氧化还原信号转导能力更加神秘。这是一个亟待解决的关键差距 因为在疾病发病机制中,在正确的时间阻止高度特异的氧化还原信号形式可以防止 肾细胞功能障碍。我们的中心假设是LOOH是关键的代谢信号,它传递最初的 细胞中的氧化还原应激。此外,我们认为糖尿病改变了LOOH的分子特征,并且 从无数不同的氧化磷脂中,只有几个特定的磷脂决定激活 程序性细胞死亡。我们主要研究近端肾小管上皮细胞(PTC),它约占肾小管上皮细胞总数的70-80%。 在那里,我们以前发现PTC代谢的失调会增强LOOH的产生。 我们有大量的初步数据表明,当PTC代谢受到脂质挑战时 过载或通过删除谷胱甘肽来破坏膜过氧化物膜的中和机制 过氧化物酶4(Gpx4)、LOOH产生过多,导致小鼠肾脏损伤。使用糖尿病模型,我们 表明糖尿病不仅促进了LOOH的形成,而且还改变了 LOOH物种氧化磷脂酰乙醇胺(PE)和溶血磷脂酰乙醇胺 (LPE)变得丰富。三个目标将使用最先进的生物物理和质量来验证这一假说 光谱成像方法与药理学和转基因方法相结合 已建立和新生成的小鼠模型。在目标1中,我们将测试PTC变化的预测 代谢活动调节LOOH的产生。AIM 2将探索糖尿病通过 促进特定含氧磷脂的产生。在目标3中,我们将检验假设,即 磷脂物种的选择性氧化决定了肾细胞死亡程序的激活。这个 实验策略结合了PTC特定的转基因模型、肥胖的CKD和糖尿病的DKD模型,使用 靶向化合物去除氧化还原应激和高级氧化还原磷脂组学的起源 和生物物理方法。这项提案的结果将建立一个新的、更具体的氧化还原观点 CKD/DKD中的应激,并将特定的氧化(磷)脂与PTC损伤和死亡联系起来,为 未来高特异性的抗细胞凋亡或抗铁下垂干预措施。

项目成果

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Krisztian Stadler其他文献

Krisztian Stadler的其他文献

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{{ truncateString('Krisztian Stadler', 18)}}的其他基金

Mitochondrial overload and proximal tubular cell atrophy
线粒体过载和近端肾小管细胞萎缩
  • 批准号:
    10159897
  • 财政年份:
    2018
  • 资助金额:
    $ 29.98万
  • 项目类别:
Lipid peroxidation-induced chemical modifications of insulin signaling proteins
脂质过氧化诱导的胰岛素信号蛋白化学修饰
  • 批准号:
    8327262
  • 财政年份:
    2010
  • 资助金额:
    $ 29.98万
  • 项目类别:
Lipid peroxidation-induced chemical modifications of insulin signaling proteins
脂质过氧化诱导的胰岛素信号蛋白化学修饰
  • 批准号:
    8142216
  • 财政年份:
    2010
  • 资助金额:
    $ 29.98万
  • 项目类别:
Lipid peroxidation-induced chemical modifications of insulin signaling proteins
脂质过氧化诱导的胰岛素信号蛋白化学修饰
  • 批准号:
    8119876
  • 财政年份:
    2010
  • 资助金额:
    $ 29.98万
  • 项目类别:

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中链酰基辅酶 A 脱氢酶作为多形性胶质母细胞瘤的重要饲养者
  • 批准号:
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    1996
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