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

• 批准号: 10253060
• 负责人: Maria V Irazabal
• 金额: $ 10万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10253060
• 关键词: 3-Dimensional; Address; Adult; Affect; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Autosomal Dominant Polycystic Kidney; Basic Science; Bilateral; Biological Markers; CREB1 gene; Clinical; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cystic kidney; Data; Development; Disease; Disease Progression; Early identification; Electron Microscopy; Endothelial Cells; Environment; Enzymes; Epithelial Cells; Evaluation; Excision; Functional disorder; Goals; Healthcare Systems; Injury; Intervention; Isoprostanes; Kidney; Kidney Diseases; Kidney Failure; Manuscripts; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Mitochondrial DNA; Modeling; Monitor; Mus; Mutation; NADPH Oxidase; Nephrons; Organelles; Outcome; Oxidation-Reduction; Oxidative Stress; PKD1 gene; PKD2 gene; PKD2 protein; Pathway interactions; Patients; Pharmacology; Phenotype; Process; Production; Proteins; Rattus; Reactive Oxygen Species; Role; Severity of illness; Signal Transduction; Signaling Molecule; Structure; Surrogate Markers; Techniques; Testing; Therapeutic Intervention; Time; Up-Regulation; Urine; cost; early detection biomarkers; follow-up; functional loss; indexing; novel; novel marker; novel therapeutics; polycystic kidney disease 1 protein; protein activation; renal epithelium; specific biomarkers; targeted treatment; therapeutic target; treatment effect; treatment response

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.

常染色体显性多囊性肾脏疾病（ADPKD）是一种毁灭性的全身性疾病，导致 美国医疗保健系统每年约33亿美元。它的特征是渐进式 双侧肾囊肿的发展和扩大导致肾衰竭。早期的肾单位保护 策略可能会改变疾病的进程，但导致疾病严重程度和 进展尚未完全阐明，从而限制了新疗法的发展。此外，下面 由于表型较大，对患者的治疗反应的UP和评估代表了一个重大挑战 可变性，疾病的自然过程以及当前可用的生物标志物的局限性。它一直 提出功能性polycystin-1和polycystin-2（主要ADPKD蛋白产物）的损失导致降低 细胞内Ca+2，cAMP积累和蛋白激酶A（PKA）信号的激活。此外，ADPKD 与肾脏活性氧（ROS），线粒体异常和 早期对疾病的代谢失调，可能会影响疾病进展。之间的连接 这些过程仍未解决。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，氧化还原环境由ROS的产生和去除决定 ROS激活或停用各种酶和信号分子的能力。我们的初步数据 PKD1RC/RC小鼠在肾脏ROS生产者NADPH氧化酶4（NOX4）中显示早期上调，与 线粒体异常和代谢失调与疾病严重程度和 进展。在PKD1RC/RC模型中，NOX4上调和代谢异常更为明显 随着PKA的本构上调，与表现出上调的内皮细胞中先前的研究一致 NOX4通过CAMP/PKA/CREB依赖性途径的of。 NOX4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信号的激活是否导致 NOX4上调尚不清楚。我们的中心假设是PKA介导的NOX4上调， 动态调节诱导线粒体异常和的细胞氧化还原环境 代谢失调，并导致疾病的严重程度和进展。三个具体目标将 被追捕：目标1：将确定NOX4在细胞氧化还原环境，线粒体结构中的影响 ADPKD中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信号的激活是否诱导ADPKD的早期NOX4上调。目标3：意志 确定尿液NOX4，线粒体损伤的替代标记和氧化应激是否有用 实时生物标志物评估早期ADPKD患者的疾病严重程度和进展。成功的 通过促进对ROS在ADPKD中的作用的理解，研究将具有重要的临床意义。 提供潜在的可修改治疗靶标，并识别ADPKD中新型的早期生物标志物。