Regulation of renal Na+ excretion by antidiuretic hormone

抗利尿激素对肾脏Na排泄的调节

• 批准号: 8836135
• 负责人: Elena Mironova
• 金额: $ 6.1万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836135
• 关键词: Address; Adrenal gland hypofunction; Affect; Aldosterone; Biological; Blood Pressure; Body Water; Clinical Treatment; Consumption; Data; Disease; Distal; Dose; Duct (organ) structure; Elderly; Electrolytes; Epithelial; Equilibrium; Excretory function; Feedback; Financial compensation; Functional disorder; Goals; Health; Homeostasis; Hormones; Hypernatremia; Hyponatremia; Inappropriate ADH Syndrome; Kidney; Knowledge; Laboratory Finding; Lead; Life; Limb structure; Mammals; Morbidity - disease rate; Nephrons; Osmolalities; Osmosis; Outcome; Pathology; Patients; Permeability; Physiological; Physiological Processes; Plasma; Process; Publishing; Regulation; Renin-Angiotensin-Aldosterone System; Research; Role; Saline; Serum; Sodium; Sodium Channel; Testing; Thick; Urine; Vasopressins; Water; Water-Electrolyte Balance; Water-Electrolyte Imbalance; Work; aquaporin-2; base; biological systems; effective therapy; epithelial Na+ channel; hypertensive heart disease; insight; kidney vascular structure; mortality; novel; programs; public health relevance; response; saluretic; tool; wasting; water channel

DESCRIPTION (provided by applicant): My goal is to direct an independent research program focused on understanding mechanisms of Na+ and water regulation in the kidney. The proposed studies address the mechanisms of renal Na+ regulation by antidiuretic hormone (ADH) during hyponatremia which is a common electrolyte abnormality with a potential for high morbidity and mortality. Because much about the fundamental mechanisms enabling differential control of Na+ and water excretion by the kidney remains obscure, current treatment of hyponatremia often is not fully effective. Serum Na+ is maintained by homeostatic mechanisms that involve discretionary water and Na+ reabsorption by the kidney which are regulated by ADH and the renin-angiotensin- aldosterone (RAAS) system, respectively. Recent findings demonstrate that ADH also directly affects renal Na+ excretion. Pharmacological tools capable of separating the actions of ADH on renal Na+ and water excretion currently do not exist, complicating treatment of hyponatremia. Plasma Na+ and osmolality are fine-tuned in the distal nephron by negative-feedback regulation of Na+ and free water excretion. ADH stimulates aquaporin 2 (AQP2) water channels to increase the water permeability of the distal nephron and generates an axial corticomedullary hyperosmotic gradient that draws water from this segment. In this regard, ADH is anti- aquaretic concentrating urine to decrease plasma osmolality. Emerging evidence suggests that Na+ reabsorbed through ADH-stimulated ENaC contributes to the hyperosmotic gradient during the fine-tuning of urine concentration, which makes ENaC activation in this sense also anti-aquaretic. However, much about the contribution of ENaC to decreases in free water excretion is obscure and seems counterintuitive. For instance, if ADH-activated ENaC contributes to concentrating urine, then it must also contribute to hyponatremia. This seems contradictory to the accepted role of ENaC as having a positive effect on plasma Na+. Moreover, in hypernatremic states where ADH is elevated as a feedback response, activation of ENaC would either exacerbate this condition if it positively influences plasma Na+ or work in compensation if it facilitates urine concentration. A unifying paradigm, as tested here, is that the consequences of activating ENaC depend on whether it is activated in the presence of working AQP2 where ADH stimulates both. The novel hypothesis that activation of ENaC by ADH shifts the role of this channel from primarily influencing plasma Na+ to facilitating concentration of urine and thus plasma osmolality is tested through three specific aims: (1) Determine the effective concentration of ADH on ENaC in health and pathological states; (2) Quantify the contribution of ADH-stimulated ENaC to systemic Na+ and water balance; (3) Understand the contribution of ADH-stimulated ENaC to pathologycal states of hypo- and hypernatremia. Completing these aims will provide mechanistic insight into a fundamental physiological process regulating renal Na+ and water excretion and systemic Na+ and water balance.

描述（由申请人提供）：我的目标是指导一个独立的研究项目，重点是了解肾脏中 Na+ 和水的调节机制。拟议的研究探讨了低钠血症期间抗利尿激素 (ADH) 调节肾 Na+ 的机制，低钠血症是一种常见的电解质异常，可能导致高发病率和死亡率。由于肾脏差异控制 Na+ 和水排泄的基本机制仍然不清楚，目前低钠血症的治疗通常并不完全有效。血清 Na+ 通过稳态机制维持，该机制涉及肾脏对水和 Na+ 的选择性重吸收，分别受 ADH 和肾素-血管紧张素-醛固酮 (RAAS) 系统的调节。最近的研究表明，ADH 还直接影响肾脏 Na+ 排泄。目前尚不存在能够分离 ADH 对肾脏 Na+ 和水排泄作用的药理学工具，这使得低钠血症的治疗变得复杂化。血浆 Na+ 和渗透压在远端肾单位中通过 Na+ 和自由水排泄的负反馈调节进行微调。 ADH 刺激水通道蛋白 2 (AQP2) 水通道，增加远端肾单位的水渗透性，并产生轴向皮质髓质高渗梯度，从该部分吸取水。在这方面，ADH 是抗水剂，浓缩尿液以降低血浆渗透压。新出现的证据表明，通过 ADH 刺激的 ENaC 重吸收的 Na+ 有助于在尿液浓度微调过程中形成高渗梯度，这使得 ENaC 激活在这个意义上也具有反水作用。然而，ENaC 对自由水排泄减少的贡献尚不清楚，而且似乎违反直觉。例如，如果 ADH 激活的 ENaC 有助于浓缩尿液，那么它也一定会导致低钠血症。这似乎与公认的 ENaC 对血浆 Na+ 具有积极作用的作用相矛盾。此外，在高钠血症状态下，ADH 作为反馈反应而升高，ENaC 的激活如果对血浆 Na+ 产生积极影响，就会加剧这种情况；如果 ENaC 促进尿液浓缩，就会起到补偿作用。一个统一的范式，正如这里所测试的， 激活 ENaC 的后果取决于它是否在 AQP2 存在的情况下被激活，而 ADH 刺激两者。新的假设是，ADH 激活 ENaC 会将该通道的作用从主要影响血浆 Na+ 转变为促进尿液浓缩，因此通过三个具体目标测试血浆渗透压：(1) 确定 ADH 对健康人和 ENaC 的有效浓度。病理状态； (2) 量化 ADH 刺激的 ENaC 对系统 Na+ 和水平衡的贡献； (3) 了解 ADH 刺激的 ENaC 对低钠血症和高钠血症病理状态的贡献。完成这些目标将为调节肾脏 Na+ 和水排泄以及全身 Na+ 和水平衡的基本生理过程提供机制见解。