Role of NOX4 and redox environment in Autosomal Dominant Polycystic Kidney Disease

NOX4 和氧化还原环境在常染色体显性多囊肾病中的作用

基本信息

  • 批准号:
    10253060
  • 负责人:
  • 金额:
    $ 10万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-15 至 2022-03-14
  • 项目状态:
    已结题

项目摘要

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating systemic disorder, resulting in approximately $3.3 billion cost per year to the US health care system. It is characterized by progressive development and enlargement of bilateral renal cysts leading to renal failure. Early nephron-protective strategies may alter the course of the disease, but the mechanisms contributing to disease severity and progression remain to be fully elucidated, limiting the development of new therapies. Furthermore, the follow up and evaluation of a treatment response in patients represents a major challenge due to the large phenotypic variability, the natural course of the disease and limitations in currently available biomarkers. It has been proposed that loss of functional polycystin-1 and polycystin-2 (main ADPKD protein products) result in reduced intracellular Ca+2, cAMP accumulation and activation of protein kinase A (PKA) signaling. In addition, ADPKD has been associated with increased renal reactive oxygen species (ROS), mitochondrial abnormalities and metabolic dysregulations early on the disease, likely influencing disease progression. The connection between these processes remains unresolved. Intracellular signaling, organelles, and metabolic pathways are influenced by the redox environment, which is determined by the production and removal of ROS, due to ROS's ability to activate or deactivate a variety of enzymes and signaling molecules. Our preliminary data in Pkd1RC/RC mice shows an early upregulation in renal ROS producer NADPH oxidase 4 (NOX4), associated with mitochondrial abnormalities and metabolic dysregulations that correlates with disease severity and progression. NOX4 upregulation and metabolic abnormalities were more pronounced in a Pkd1RC/RC model with constitutive upregulation of PKA, consistent with previous studies in endothelial cells showing upregulation of NOX4 via cAMP/PKA/CREB-dependent pathway. How NOX4 affects the cellular redox environment and its influence in mitochondrial function and metabolic pathways, and whether activation of PKA signaling leads to NOX4 upregulation are not known. Our central hypothesis is that PKA-mediated NOX4 upregulation, dynamically regulates the cellular redox environment inducing mitochondrial abnormalities and metabolic dysregulations, and contributes to disease severity and progression. Three specific aims will be pursued: Aim 1: will determine the impact of NOX4 in cellular redox environment, mitochondria structure and function and metabolic pathways in ADPKD and the contribution to disease severity and progression. Aim 2: will test whether activation of PKA signaling induces early NOX4 upregulation in ADPKD. Aim 3: will determine whether urine NOX4, surrogate markers of mitochondria injury and oxidative stress may be useful real-time biomarkers to assess disease severity and progression in patients with early ADPKD. Successful studies will have important clinical implications by advancing the understanding of the role of ROS in ADPKD, providing potentially modifiable therapeutic target and identifying novel early biomarkers in ADPKD.
常染色体显性多囊肾病(ADPKD)是一种破坏性的全身性疾病, 每年为美国医疗保健系统带来约33亿美元的成本。它的特点是渐进的 肾囊肿是一种慢性肾功能衰竭的疾病。早期肾单位保护 策略可能会改变疾病的进程,但导致疾病严重程度和 进展仍有待充分阐明,限制了新疗法的发展。此外,以下 由于大的表型差异, 变异性、疾病的自然病程和目前可用的生物标志物的局限性。已经 提出多囊蛋白-1和多囊蛋白-2(ADPKD的主要蛋白产物)的功能丧失导致ADPKD的减少, 细胞内Ca+2、cAMP积累和蛋白激酶A(PKA)信号传导的活化。此外,ADPKD 与肾活性氧(ROS)增加、线粒体异常和 疾病早期代谢失调,可能影响疾病进展。之间的连接 这些进程仍未解决。细胞内信号传导、细胞器和代谢途径是 受氧化还原环境的影响,这是由ROS的产生和去除决定的,由于 活性氧激活或灭活多种酶和信号分子的能力。我们的初步数据, Pkd 1 RC/RC小鼠显示肾ROS产生者NADPH氧化酶4(NOX 4)的早期上调,与 与疾病严重程度相关的线粒体异常和代谢失调, 进展在Pkd 1 RC/RC模型中,NOX 4上调和代谢异常更为明显 PKA的组成性上调,与先前在内皮细胞中显示上调的研究一致 通过cAMP/PKA/CREB依赖的途径。NOX 4如何影响细胞氧化还原环境及其 线粒体功能和代谢途径的影响,以及PKA信号传导的激活是否导致 NOX 4的上调是未知的。我们的中心假设是PKA介导的NOX 4上调, 动态调节诱导线粒体异常的细胞氧化还原环境, 代谢失调,并有助于疾病的严重性和进展。三个具体目标将 目标1:确定NOX 4对细胞氧化还原环境、线粒体结构的影响 以及ADPKD的功能和代谢途径以及对疾病严重程度和进展的贡献。目的 2:将测试PKA信号传导的激活是否诱导ADPKD中的早期N 0X 4上调。目标3:意愿 确定尿NOX 4、线粒体损伤和氧化应激的替代标志物是否有用 实时生物标志物,以评估早期ADPKD患者的疾病严重程度和进展。成功 这些研究将通过促进对ROS在ADPKD中作用的理解而具有重要的临床意义, 提供了潜在的可改变的治疗靶点并鉴定了ADPKD的新的早期生物标志物。

项目成果

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Maria V Irazabal其他文献

Maria V Irazabal的其他文献

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{{ truncateString('Maria V Irazabal', 18)}}的其他基金

Role of homocysteine metabolism, endothelial function and microvascular rarefaction on renal disease severity and progression in ADPKD
同型半胱氨酸代谢、内皮功能和微血管稀疏对 ADPKD 肾脏疾病严重程度和进展的作用
  • 批准号:
    10398925
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:
Noninvasive evaluation of the intrarenal microvasculature in ADPKD
ADPKD 肾内微血管的无创评估
  • 批准号:
    10456178
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:
Noninvasive evaluation of the intrarenal microvasculature in ADPKD
ADPKD 肾内微血管的无创评估
  • 批准号:
    10282783
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:
Role of homocysteine metabolism, endothelial function and microvascular rarefaction on renal disease severity and progression in ADPKD
同型半胱氨酸代谢、内皮功能和微血管稀疏对 ADPKD 肾脏疾病严重程度和进展的作用
  • 批准号:
    10176910
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:
Role of homocysteine metabolism, endothelial function and microvascular rarefaction on renal disease severity and progression in ADPKD
同型半胱氨酸代谢、内皮功能和微血管稀疏对 ADPKD 肾脏疾病严重程度和进展的作用
  • 批准号:
    10598067
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:
Role of Fumarate and Nrf2 response in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease
富马酸和 Nrf2 反应在常染色体显性多囊肾发病机制中的作用
  • 批准号:
    9767587
  • 财政年份:
    2018
  • 资助金额:
    $ 10万
  • 项目类别:
Role of Fumarate and Nrf2 response in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease
富马酸和 Nrf2 反应在常染色体显性多囊肾发病机制中的作用
  • 批准号:
    9583066
  • 财政年份:
    2018
  • 资助金额:
    $ 10万
  • 项目类别:

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