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.

常染色体显性多囊肾病 (ADPKD) 是一种毁灭性的系统性疾病，可导致 美国医疗保健系统每年花费约 33 亿美元。其特点是渐进式 双侧肾囊肿的发展和扩大导致肾功能衰竭。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影响的机制 进展仍有待充分阐明，限制了新疗法的开发。此外，以下 由于表型较大，因此对患者的治疗反应进行评估是一项重大挑战 变异性、疾病的自然病程以及当前可用生物标志物的局限性。它一直 提出功能性多囊蛋白-1 和多囊蛋白-2（主要 ADPKD 蛋白产物）的丧失导致 细胞内 Ca+2、cAMP 积累和蛋白激酶 A (PKA) 信号传导的激活。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。之间的联系 这些进程仍未得到解决。细胞内信号传导、细胞器和代谢途径 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，由于 ROS 具有激活或失活多种酶和信号分子的能力。我们的初步数据在 Pkd1RC/RC 小鼠显示肾脏 ROS 产生者 NADPH 氧化酶 4 (NOX4) 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。 NOX4 上调和代谢异常在 Pkd1RC/RC 模型中更为明显 与 PKA 的组成性上调相一致，与之前显示上调的内皮细胞研究一致 NOX4 通过 cAMP/PKA/CREB ​​依赖性途径。 NOX4如何影响细胞氧化还原环境及其 对线粒体功能和代谢途径的影响，以及 PKA 信号的激活是否会导致 NOX4 上调尚不清楚。我们的中心假设是 PKA 介导的 NOX4 上调， 动态调节细胞氧化还原环境，诱导线粒体异常 代谢失调，并导致疾病的严重性和进展。三个具体目标将 目标1：确定NOX4对细胞氧化还原环境、线粒体结构的影响 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 信号传导的激活是否会诱导 ADPKD 中早期 NOX4 上调。目标3：将 确定尿液 NOX4、线粒体损伤和氧化应激的替代标志物是否有用 实时生物标记物可评估早期 ADPKD 患者的疾病严重程度和进展。成功的 通过增进对 ROS 在 ADPKD 中作用的理解，研究将具有重要的临床意义， 提供潜在可修改的治疗靶点并识别 ADPKD 的新型早期生物标志物。