Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure

减少慢性心力衰竭钠潴留的新靶点机制（去肾神经）

• 批准号: 9365386
• 负责人: KAUSHIK P PATEL
• 金额: $ 41.24万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365386
• 关键词: Address; Aldosterone; Angiotensin II; Animals; Canis familiaris; Cardiac; Cells; Clinical; Congestive; Congestive Heart Failure; Data; Denervation; Deubiquitination; Disease Progression; Diuretics; Dyspnea; Edema; Elements; Equilibrium; Experimental Models; Fatigue; Impairment; Kidney; Liquid substance; Measurement; Mediating; Methodology; Molecular; Molecular Biology Techniques; Nausea; Nerve; Norepinephrine; Patients; Peptide Hydrolases; Physiological; Protease Inhibitor; Rattus; Regulation; Renal function; Renal tubule structure; Renin-Angiotensin System; Role; Serine Protease; Sodium; Symptoms; Syndrome; System; Testing; Therapeutic; Tubular formation; Ubiquitination; Urine; Water; base; benzamil; epithelial Na+ channel; hemodynamics; inhibitor/antagonist; insight; novel; podocyte; protein expression; response; saluretic; urinary

Project Summary One hallmark feature of chronic heart failure (CHF) is sodium and fluid retention. While the cardio-renal syndrome has been recognized, a comprehensive understanding of the precise cellular mechanisms contributing to sodium and water retention in CHF remains elusive. Renal denervation (RDN) has been shown to reduce sodium retention in rats and dogs with CHF. One of the key elements involved in renal sodium retention is activation of epithelial sodium channels (ENaC) of principal cells in the collecting tubule. We have previously shown that ENaC subunit expressions and activity were increased in the kidneys from rats with CHF. We have recent evidence indicating that increased proteases in the tubular fluid may contribute to the enhanced renal ENaC activity, providing a novel mechanistic insight for sodium retention commonly observed in CHF. We have observed that in rats with CHF: 1) the levels of serine proteases were dramatically increased in the urine; 2) protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Furthermore, our preliminary data have shown that RDN decreased the levels of proteases in the urine, reduced protein expressions of ENaC subunits in the kidney of CHF rats, supporting the potential role of sympathetic nerve activation. Based on these data, we will test the hypothesis that RDN reduces renal sodium retention in CHF rats by modulation of the ENaC and protease-ENaC axis. In AIM 1 we will determine the contribution of RDN in the expression/inactivation of ENaC in rats with CHF rats. In AIM 2 we will determine the contribution of tubular proteases in activating ENaC in rats with CHF. These aims will be addressed in rats with CHF using complementary methodologies ranging from cellular to the whole animal level, including physiological measurement of sodium balance, ENaC activity, eletrophysiological recording, protease and ubiquitination of ENaC using molecular biology techniques. The successful completion of the proposed studies will provide significant new information and insight into the contribution of ENaC regulation in altered sodium balance in CHF and the therapeutic benefits of RDN on sodium fluid retention, endemic to CHF.

项目摘要 慢性心力衰竭（CHF）的一个标志性特征是钠和液体保留率。而心肾脏 综合征已被认可，对精确的细胞机制有了全面的理解 在CHF中有助于钠和水分retention留仍然难以捉摸。肾脏神经（RDN）已显示 为了减少带有CHF的大鼠和狗中的钠保留率。肾钠涉及的关键要素之一 保留是收集小管中主要细胞的上皮钠通道（ENAC）的激活。我们有 先前表明的ENAC亚基表达和活性在大鼠的肾脏中增加了 瑞士法郎。我们最近有证据表明，管状液中蛋白酶的增加可能有助于 增强的肾脏ENAC活性，为钠保留提供了一种新颖的机械洞察力 在瑞士法郎。我们观察到，在具有CHF的大鼠中：1）丝氨酸蛋白酶的水平急剧增加 在尿液中； 2）蛋白酶抑制剂治疗显着废除了增强的利尿剂和脂肪尿剂 CHF大鼠中对ENAC抑制剂苯甲胺的反应。此外，我们的初步数据表明 RDN降低了尿液中蛋白酶的水平，降低了ENAC亚基的蛋白质表达 CHF大鼠的肾脏，支持交感神经激活的潜在作用。基于这些数据，我们将 测试RDN通过调节来降低CHF大鼠中肾脏钠的保留率的假设 和蛋白酶-ENAC轴。在AIM 1中，我们将确定RDN在表达/灭活中的贡献 带有CHF大鼠的大鼠的ENAC。在AIM 2中，我们将确定管状蛋白酶在激活ENAC中的贡献 在带有瑞士法郎的大鼠中。这些目标将使用CHF使用互补方法来解决。 从细胞到整个动物水平，包括钠平衡的生理测量，ENAC活性， 使用分子生物学技术对ENAC的eletrophyolyology记录，蛋白酶和泛素化。这 成功完成拟议的研究将为您提供重要的新信息和洞察力 ENAC调节在CHF中钠平衡改变的贡献以及RDN的治疗益处 保留钠，CHF特有。