NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult

NOX4相关的氧化应激介导低出生体重成人的血管和肾脏损伤

• 批准号: 10320920
• 负责人: Brian Blake Ratliff
• 金额: $ 41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320920
• 关键词: Ablation; Adult; Aminolevulinic Acid; Animals; Automobile Driving; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic Kidney Failure; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Female; Functional disorder; Gender; Generations; Genetic; HMGB1 gene; Human; Hypertension; Hypertrophy; Impairment; Inflammation; Interleukin-1 beta; Intervention; Kidney; Kidney Diseases; Lead; Low Birth Weight Infant; Measurement; Mediating; Medicine; Membrane; Metabolic; Mitochondria; Mitochondrial Matrix; Modeling; Mus; NADP; NADPH Oxidase; Neonatal; Nitric Oxide; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Pathologic; Pathology; Pathway interactions; Perfusion; Population; Process; Regulation; Renal Blood Flow; Renal Hypertension; Renal function; Respiration; Role; Signal Transduction; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Sulfhydryl Compounds; Superoxides; System; TLR4 gene; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Vascular Diseases; driving force; endothelial dysfunction; ethyl pyruvate; experience; experimental study; heme biosynthesis; inhibitor; iron metabolism; kidney dysfunction; kidney fibrosis; kidney vascular structure; male; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; offspring; oxidation; pregnant; prevent; sensor; tempol; vasoconstriction

PROJECT ABSTRACT Recent advances in neonatal medicine have increased the population of low birth weight (LBW) babies that are incredibly susceptible for development of hypertension, cardiovascular disease and chronic kidney disease for unknown reasons as they mature through adulthood. Using an undernourished pregnant mouse model to generate LBW offspring that develop pathologies similar to those in LBW humans, the proposed studies will investigate the association of vascular and kidney disease in the LBW adult with systems regulated by oxidative stress. The study will also examine new potential therapeutic strategies that target vascular oxidant- regulated mechanisms to treat hypertension and renal dysfunction. Our current studies have provided evidence for NADPH oxidase-4 (NOX4) driven increases in superoxide-mediated endothelial nitric oxide dysfunction, thiol oxidation-mediated release of HMGB1 (which potentially activates TLR4) and IL-1β promoted inflammation as potential driving factors in the disease progression that the LBW adult experiences. Studies in Aim 1 will examine the consequences of LBW in Nox4 deficient mice and in LBW mice treated with agents that inhibit NOX4, scavenge superoxide (including superoxide in the mitochondrial matrix), stabilize cytosolic NADPH redox, and promote heme biosynthesis to define their impact on vascular dysfunction, impairment of renal perfusion and hypertension development. Measurements of a) redox and metabolic indicators or signaling mechanisms related to these approaches, b) alterations in vascular function, and c) alterations in tissue mitochondrial respiration and function will be made to help define driving forces in the progression of vascular and renal dysfunction that is observed. Using mice deficient in TLR4, and animals treated with inhibitors of HMGB1 release, TLR4 and IL-1β, studies in Aim 2 will focus on defining the role that the redox sensor HMGB1 has in causing inflammation, vascular rarefaction, renal fibrosis and glomerular hypertrophy associated with hypertension and kidney disease. Supporting mechanisms for the HMGB1-TLR4 activation processes will be defined in cells cultured from control and LBW animals. Studies in this aim will examine the role of TLR4 in the actions of oxidized forms of HMGB1, and the impact of TLR4 activation on endothelial cell mitochondrial dysfunction and release of IL-1β. The approaches and measurements made in Aim 1 will also be used to document the impact of the interventions in Aim 2 on relationships between redox regulatory processes and aspects of disease progression. It is hypothesized that the redox changes in HMGB1 (identified by mass spectral analyses) can potentially be modulated by the therapies employed in ways that could help define the HMGB1 redox forms that are the most pathologically active. It is anticipated that the studies proposed will document and define the driving factors that promote the progression of hypertension, cardiovascular and chronic kidney disease in LBW adults, in addition to identifying novel therapeutic approaches that target the systems that drive such disease progression.

项目摘要 新生儿医学的最新进展增加了低出生体重(LBW)婴儿的数量 极易发展为高血压、心血管疾病和慢性肾脏疾病 未知的原因，因为他们在成年后逐渐成熟。使用营养不良的怀孕小鼠模型 产生与LBW人类相似的LBW后代，拟议的研究将 研究LBW成人的血管和肾脏疾病与以下调节系统的关系 氧化应激。这项研究还将研究针对血管氧化剂的新的潜在治疗策略- 治疗高血压和肾功能障碍的调节机制。我们目前的研究提供了 NADPH氧化酶-4(NOX4)导致超氧化物介导的内皮一氧化氮增加的证据 功能障碍，硫醇氧化介导的HMGB1(可能激活TLR4)和IL-1β的释放促进 炎症是LBW成人经历的疾病进展的潜在驱动因素。研究项目： 目标1将研究低体重在NOX4缺陷小鼠和低体重小鼠中的后果，这些药物治疗 抑制NOX4，清除超氧化物(包括线粒体基质中的超氧化物)，稳定胞浆 NADPH氧化还原，并促进血红素的生物合成，以确定其对血管功能障碍的影响 肾血流灌注与高血压的发生。A)氧化还原和代谢指标的测量或 与这些途径相关的信号机制，b)血管功能的改变，以及c) 组织线粒体的呼吸和功能将有助于确定进展的驱动力 观察到的血管和肾功能障碍。使用TLR4基因缺陷的小鼠，并用 HMGB1释放的抑制剂，TLR4和IL-1β，在Aim 2的研究将集中在定义氧化还原的作用 传感器HMGB1在引起炎症、血管稀疏、肾纤维化和肾小球肥大方面具有重要作用 与高血压和肾脏疾病有关。HMGB1-TLR4激活的支持机制 过程将在对照组和LBW动物的细胞培养中定义。这一目标的研究将审查 TLR4在氧化型HMGB1作用中的作用及TLR4活化对内皮细胞的影响 线粒体功能障碍与IL-1β的释放。目标1中的方法和措施也将是 用于记录AIM 2中的干预措施对氧化还原调节之间关系的影响 疾病进展的过程和方面。假设HMGB1中的氧化还原变化(已确定 通过质谱分析)可以潜在地被所采用的疗法调制，其方式可能有助于 定义病理上最活跃的HMGB1氧化还原形式。预计这些研究将 提议将记录和定义促进高血压进展的驱动因素， 除了确定新的治疗方法外，LBW成人的心血管和慢性肾脏疾病 针对推动这种疾病进展的系统的方法。