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+和水调节的机制。拟定研究探讨了低钠血症期间抗利尿激素（ADH）对肾脏Na+调节的机制，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。由于许多关于能够通过肾脏对Na+和水排泄进行差异控制的基本机制仍然不清楚，因此目前对低钠血症的治疗通常不是完全有效的。血清Na+通过稳态机制维持，该稳态机制涉及肾脏的自由选择性水和Na+重吸收，其分别由ADH和肾素-血管紧张素-醛固酮（RAAS）系统调节。最近的研究表明，ADH也直接影响肾脏Na+排泄。目前尚不存在能够分离ADH对肾Na+和水排泄的作用的药理学工具，使低钠血症的治疗复杂化。通过Na+和游离水排泄的负反馈调节，在远端肾单位中对血浆Na+和渗透压进行微调。ADH刺激水通道蛋白2（AQP 2）水通道，以增加远端肾单位的水渗透性，并产生轴向皮髓质高渗梯度，从该部分吸取水分。在这方面，ADH是抗利尿剂，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+有助于在微调尿液浓度期间的高渗梯度，这使得ENaC激活在这个意义上也抗aquaretic。然而，关于ENaC对自由水排泄减少的贡献是模糊的，似乎违反直觉。例如，如果ADH激活的ENaC有助于浓缩尿液，那么它也必须有助于低钠血症。这似乎与ENaC对血浆Na+具有积极作用的公认作用相矛盾。此外，在ADH作为反馈反应升高的高钠血症状态下，如果ENaC对血浆Na+产生积极影响，则ENaC的激活会加剧这种情况，或者如果ENaC促进尿液浓缩，则ENaC的激活会起到补偿作用。一个统一的范例，正如这里所测试的， 激活ENaC的结果取决于它是否在存在工作AQP 2的情况下被激活，其中ADH刺激两者。ADH激活ENaC的新假设将该通道的作用从主要影响血浆Na+转变为促进尿液浓缩，从而通过三个特定目的测试血浆渗透压：（1）确定健康和病理状态下ADH对ENaC的有效浓度;（2）量化ADH刺激的ENaC对全身Na+和水平衡的贡献;（3）了解ADH刺激的ENaC在低钠血症和高钠血症病理状态中的作用。完成这些目标将提供一个基本的生理过程，调节肾脏Na+和水的排泄和全身Na+和水的平衡机制的见解。