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潴留。而心肾 综合症已被认识，对精确细胞机制的全面了解 导致CHF中钠和水保留的原因仍然是难以捉摸的。肾脏去神经支配（RDN）已被证明 减少CHF大鼠和犬的钠潴留。参与肾钠的关键元素之一 滞留是集合小管中主细胞的上皮钠通道（ENaC）的激活。我们有 先前的研究表明，ENaC亚单位的表达和活性在患有糖尿病的大鼠肾脏中增加， 瑞士法郎。我们最近有证据表明，肾小管液中蛋白酶的增加可能有助于 增强肾脏ENaC活性，为常见的钠潴留提供了一种新的机制见解 单位：瑞士法郎。我们已经观察到，在CHF大鼠中：1）丝氨酸蛋白酶的水平显著增加， 蛋白酶抑制剂治疗显著消除了增强的利尿剂和利钠剂， 对ENaC抑制剂苯扎米尔的反应。此外，我们的初步数据显示， RDN降低尿中蛋白酶的水平，减少ENaC亚单位的蛋白表达， CHF大鼠肾脏，支持交感神经激活的潜在作用。根据这些数据，我们将 检验RDN通过调节ENaC降低CHF大鼠肾钠潴留的假设 和蛋白酶-ENaC轴。在AIM 1中，我们将确定RDN在以下表达/失活中的作用： CHF大鼠ENaC。在AIM 2中，我们将确定肾小管蛋白酶在激活ENaC中的作用。 在CHF大鼠中。这些目标将在CHF大鼠中使用补充方法来解决， 从细胞到整个动物水平，包括钠平衡，ENaC活性， ENaC的电生理记录、蛋白酶和泛素化。的 成功完成拟议的研究将提供重要的新信息和洞察力， ENaC调节在CHF钠平衡改变中的作用以及RDN对CHF的治疗益处 钠液体潴留，CHF特有。