Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension

心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力

• 批准号: 10442162
• 负责人: Daria Ilatovskaya
• 金额: $ 56.94万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442162
• 关键词: Acute; Address; Adipose tissue; Affect; Animal Model; Animals; Antioxidants; Atrial Natriuretic Factor; Attenuated; Bioenergetics; Biogenesis; Blood Pressure; Blood Pressure Monitors; Cells; Chronic; Clinic; Clinical Data; Cultured Cells; Cyclic GMP; Dahl Hypertensive Rats; Data; Defect; Development; Disease; Diuresis; Duct (organ) structure; Echocardiography; Electrophysiology (science); Energy Metabolism; Equilibrium; Event; Excretory function; Exhibits; Experimental Designs; Free Radical Formation; Functional disorder; Generations; Heart; Hormones; Hydrogen Peroxide; Image; Impairment; Individual; Infusion procedures; Injury to Kidney; Kidney; Knock-out; Knowledge; Link; Location; Measurement; Mediating; Metabolic; Microscopy; Mitochondria; Molecular; Molecular Biology; Muscle; Natriuretic Peptides; Nephrons; Organ; Pathologic; Pathway interactions; Peptide Signal Sequences; Permeability; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Production; Rattus; Reactive Oxygen Species; Regulation; Renal Blood Flow; Renal Tissue; Resistance; Respiration; Sodium; Sodium Chloride; Spin Trapping; Superoxides; TAC1 gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Vasodilation; attenuation; base; blood flow measurement; blood pressure reduction; blood pressure regulation; cGMP production; design; dietary salt; effective therapy; epithelial Na+ channel; heart function; high risk; hypertension treatment; improved; in vivo; metabolic abnormality assessment; mitochondrial dysfunction; novel; patch clamp; patient subsets; receptor sensitivity; recruit; renal damage; salt intake; salt sensitive; salt sensitive hypertension; treatment strategy

PROJECT SUMMARY There is no specific treatment available for the subpopulation of patients with salt sensitivity of blood pressure (BP); unfortunately, the molecular mechanisms underlying salt-sensitivity remain poorly understood. One of the major proposed mechanisms for the development of salt-sensitive (SS) hypertension involves a defect in the ability of the kidneys to excrete salt. Atrial Natriuretic Peptide (ANP) encoded by Nppa, is a hormone known to promote salt excretion and BP reduction, and there are clinical data implicating inherently low levels of ANP in the development of SS hypertension. Among other effects, ANP (via cGMP-related mechanisms) is known to be beneficial for mitochondrial bioenergetics and biogenesis. However, there is a gap in knowledge regarding the effects of ANP on mitochondria in the kidney, especially in SS hypertension. Our pilot studies demonstrated that during a high salt challenge Nppa-/- (ANP knockout) Dahl SS rats exhibit exacerbated salt-sensitivity, reduced sodium excretion, and aggravated kidney injury, which is associated with mitochondrial damage and dysfunction. We also showed that there is dysregulation of renal sodium transporters, in the Nppa-/- rats compared to wild-type controls, and the activity of the Epithelial Na+ Channel (ENaC) is elevated in the collecting ducts. Chronic ANP infusion in wild-type SS rats resulted in a dramatic attenuation of salt-induced BP increase and alleviated organ damage. We hypothesize that in SS hypertension ANP deficiency/reduced sensitivity to ANP is causative to renal mitochondrial dysfunction and associated sodium transport imbalance. To address the central hypothesis of this project, we developed three specific aims: Aim 1. Establish whether increased ANP levels are beneficial for renal salt handling and cardiac function in SS hypertension. Aim 2. Determine whether low renal cGMP level resulting from lack of ANP causes an increase in renal mitochondrial Ca2+ and reactive oxygen species (ROS). Aim 3. Test the hypothesis that disrupted Ca2+ balance and excessive ROS production by dysfunctional mitochondria affect renal sodium handling in SS hypertension. We generated abundant evidence to support these aims, created a rigorous and comprehensive experimental design and established novel cutting-edge techniques to address the hypothesis. We recruited strong collaborative expertise, and will implement a combination of whole-animal studies and in vivo techniques (blood pressure monitoring with drug infusion, metabolic studies and GFR measurements), electrophysiology (single channel and whole-cell patch-clamp of the freshly isolated nephrons and isolated mitochondria), advanced microscopy, mitochondrial spectrofluorimetry and respirometry, and routine molecular biology approaches. The successful completion of the proposed studies will unravel the novel causative mechanisms of salt-sensitivity.

项目概要 对于血压盐敏感性患者亚群，尚无特效治疗方法 （英国石油公司）；不幸的是，人们对盐敏感性的分子机制仍然知之甚少。中的一个 盐敏感性（SS）高血压的主要机制涉及到盐敏感（SS）高血压的缺陷 肾脏排泄盐的能力。心房钠尿肽 (ANP) 由 Nppa 编码，是一种已知的激素 促进盐排泄和血压降低，并且有临床数据表明 ANP 本身水平较低 SS 高血压的发展。除其他作用外，已知 ANP（通过 cGMP 相关机制） 有利于线粒体生物能量学和生物发生。然而，人们对这方面的认识存在差距。 ANP 对肾脏线粒体的影响，尤其是在 SS 高血压中。我们的试点研究表明 在高盐挑战期间，Nppa-/-（ANP 敲除）Dahl SS 大鼠表现出加剧的盐敏感性， 钠排泄减少，肾损伤加重，这与线粒体损伤和 功能障碍。我们还发现 Nppa-/- 大鼠中肾钠转运蛋白存在失调 与野生型对照相比，上皮 Na+ 通道 (ENaC) 的活性在收集细胞中升高。 管道。野生型 SS 大鼠慢性 ANP 输注可显着减弱盐引起的血压升高 并减轻器官损伤。 我们假设在 SS 高血压中，ANP 缺乏/对 ANP 的敏感性降低是导致肾衰竭的原因。 线粒体功能障碍和相关的钠转运失衡。为了解决这个问题的中心假设 项目中，我们制定了三个具体目标： 目标 1. 确定增加 ANP 水平是否有益于 SS 高血压的肾脏盐处理和心脏功能。目标 2. 确定肾脏 cGMP 水平是否较低 缺乏 ANP 会导致肾线粒体 Ca2+ 和活性氧 (ROS) 增加。 目标 3. 检验因功能失调而破坏 Ca2+ 平衡和过量 ROS 产生的假设 线粒体影响 SS 高血压肾钠处理。 我们产生了丰富的证据来支持这些目标，创建了严格而全面的实验 设计并建立新颖的尖端技术来解决该假设。我们招募了实力雄厚的 合作专业知识，并将实施整体动物研究和体内技术（血液 药物输注压力监测、代谢研究和 GFR 测量）、电生理学（单次 新鲜分离的肾单位和分离的线粒体的通道和全细胞膜片钳），高级 显微镜、线粒体荧光光谱法和呼吸测定法以及常规分子生物学方法。这 成功完成拟议的研究将揭示盐敏感性的新致病机制。