Defining the Contribution of ENaC to ADH-mediated Water and Sodium Excretion

定义 ENaC 对 ADH 介导的水和钠排泄的贡献

• 批准号: 9105117
• 负责人: ALAN C PAO
• 金额: $ 32.43万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-25 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105117
• 关键词: Adrenalectomy; Agonist; Aldosterone; Animals; Binding; Blood; Blood Pressure; Cells; Chronic; Conflict (Psychology); Disease; Distal; Duct (organ) structure; Elements; Epithelial; Equilibrium; Excretory function; Extracellular Fluid; Feedback; Gap Junctions; Homeostasis; Hypertension; Hyponatremia; Inappropriate ADH Syndrome; Infusion procedures; Kidney; Knockout Mice; Knowledge; Lead; Link; Liquid substance; Mediating; Medical; Methodology; Movement; Mus; Nature; Nephrons; Osmolalities; Outcome; Pathogenesis; Pathologic; Permeability; Plasma; Play; Positioning Attribute; Prevention; Reagent; Receptor Activation; Receptor Signaling; Regulation; Renin-Angiotensin-Aldosterone System; Research; Role; Serum; Signal Pathway; Signal Transduction; Sodium; Sodium Channel; System; Systemic blood pressure; Testing; Thinking; Thyroid Gland; Tubular formation; Urine; Vasopressins; Water; Water Movements; Wild Type Mouse; absorption; aquaporin-2; blood pressure regulation; clinically significant; collecting tubule structure; defined contribution; driving force; epithelial Na+ channel; gain of function mutation; hormone regulation; in vivo; insight; kidney interstitial tissue; kidney medulla; mouse model; novel; patch clamp; patient population; public health relevance; receptor; solute; treatment strategy; ubiquitin-protein ligase; water channel

 DESCRIPTION (provided by applicant): Antidiuretic hormone (ADH) plays a key role in regulating water balance by controlling renal water transport. ADH binds to the vasopressin-2 receptor (V2R) and increases expression of aquaporin 2 (AQP2) water channels in collecting duct cells to increase renal tubular water permeability. A steep solute corticomedullary gradient in the medullary interstitium provides the driving force for water absorption from tubular fluid in the distal nephron. We and others have demonstrated that ADH also stimulates activity of the epithelial sodium channel (ENaC) in the collecting duct and that ENaC possibly facilitates urine concentration. However, ENaC is traditionally regarded as the end-effector of the renin-angiotensin-aldosterone system (RAAS) and the final element that controls renal Na+ excretion and thus blood pressure. Yet we have shown that in some cases of hyponatremia, such as after adrenalectomy, ENaC activity is surprisingly robust. After adrenalectomy, serum ADH levels rise, leading to an increase in ADH-mediated ENaC activity. This increase in ENaC activity occurs in the absence of aldosterone, raising many new questions about ADH regulation of ENaC. The notion that ENaC can respond to both ADH and RAAS is at odds with the accepted role of this channel in merely controlling renal Na+ reabsorption and blood pressure. To reconcile the apparent conflicting roles of ADH in regulating both water and balance, we propose a unifying paradigm that defines the contribution of ENaC as a regulator of water and Na+ balance. We hypothesize that simultaneous activation of ENaC and AQP2 by ADH promotes urine concentration and plasma dilution. If parallel signaling pathways stimulate ENaC activity to a sufficiently high level, then ADH-mediated ENaC activation will induce Na+ retention beyond what is needed for urine concentration and lead to hypertension. We will use state-of-the-art methodologies (e.g., patch clamp studies of isolated split-open collecting duct in mice) and novel reagents (connecting segment/collecting duct-specific Nedd4-2 knockout mice) to test three Specific Aims: 1) Test whether ENaC contributes to pathologic renal water reabsorption and hyponatremia, 2) Test whether V2R activation can induce renal Na+ retention and high blood pressure, and 3) Test whether V2R signals through Nedd4-2 to stimulate ENaC in vivo. This proposal will provide mechanistic insights into how ADH, AQP2, and ENaC interact and ultimately control water and Na+ homeostasis. This knowledge is clinically significant because it may suggest new strategies, which are already currently available to clinicians, for the treatment of hyponatremia and hypertension.

 描述（由适用提供）：抗利尿性马内（ADH）通过控制肾脏水的运输在控制水平平衡方面起着关键作用。 ADH与加压素-2受体（V2R）结合，并在收集管道细胞中增加水通道蛋白2（AQP2）水通道的表达，以增加肾小管水的渗透性。髓质间质中的钢陡峭的固体皮层梯度提供了从管状流体中滥用水的驱动力 独特的肾单位。我们和其他人已经证明，ADH还刺激了收集管中上皮钠通道（ENAC）的活性，并且ENAC可能支持尿液浓度。然而，传统上，ENAC被视为肾素 - 血管紧张素 - 醛固酮系统（RAAS）的最终效果，以及控制肾脏Na+极端并因此血压的最终元素。然而，我们已经表明，在某些低钠血症（例如肾上腺切除术后）的ENAC活性非常强大。肾上腺切除术后血清ADH水平升高，导致ADH介导的ENAC活性增加。 ENAC活性的这种增加发生在缺乏醛固酮的情况下，引发了许多有关ADH ENAC调节的新问题。 ENAC可以对ADH和RAA的反应的观念与该通道在控制肾脏Na+吸收和血压中的公认作用背道而驰。为了调和ADH在控制水和平衡中的明显相互冲突的作用，我们提出了一个统一的范式，该范式定义了ENAC作为水和Na+平衡的监管者的贡献。我们假设通过ADH对ENAC和AQP2的简单激活促进了尿液浓度和血浆稀释。如果平行信号通路将ENAC活性刺激到足够高的水平，则ADH介导的ENAC激活将诱导Na+保留率，超出尿液浓度并导致高血压。我们将使用最先进的方法（例如，对小鼠中孤立的分开收集导管的斑块夹具研究）和新型试剂（连接段/收集段/收集导管特异性的NEDD4-2敲除小鼠）来测试三个特定目的：1）是否有助于病理肾脏繁殖+ renation insation+ renitation insation+ nata interiation nata flool vllool vllool vllool，2），2），2），2），2），2），2），2）压力和3）测试V2R是否通过NEDD4-2信号在体内刺激ENAC。该提案将提供有关ADH，AQP2和ENAC如何相互作用并最终控制水和Na+稳态的机械见解。这些知识在临床上具有重要意义，因为它可能建议临床医生可以使用的新策略来治疗低钠血症和高血压。