Regulation of renal Na+ excretion by antidiuretic hormone

描述(由申请人提供)：我的目标是指导一个独立的研究项目，重点是了解肾脏中钠和水分调节的机制。抗利尿激素(ADH)在低钠血症中对肾脏钠的调节机制是一种常见的电解质异常，具有较高的发病率和死亡率。由于肾脏对钠和水的不同控制的基本机制仍不清楚，目前对低钠血症的治疗往往并不完全有效。血钠的维持是由动态平衡机制维持的，包括自由支配的水分和肾脏对钠的重吸收，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也直接影响肾脏的钠排泄。目前尚不存在能够分离ADH对肾脏钠和水排泄作用的药理工具，这使低钠血症的治疗复杂化。血浆钠和渗透压在远端肾单位通过钠和自由水排泄的负反馈调节而微调。ADH刺激水通道蛋白2(AQP2)增加远端肾单位的水通透性，并产生轴向皮质-髓质高渗梯度，从该段吸水。在这一点上，ADH是反水浓缩尿液，以降低血浆渗透压。新的证据表明，通过ADH刺激的ENaC重新吸收的Na在尿液浓度微调过程中有助于高渗梯度，这使得ENaC在这个意义上的激活也是反水生的。然而，关于ENaC对减少游离水排泄量的贡献，人们很难理解，而且似乎是违反直觉的。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对血浆钠有积极影响的作用相矛盾。此外，在ADH作为反馈反应升高的高钠血症状态中，如果ENaC的激活对血浆Na有积极的影响，则会加剧这种情况，如果它促进尿液浓度，则会起到代偿作用。一个统一的范例，就像这里测试的那样， 激活ENaC的结果取决于它是否在工作的AQP2存在的情况下被激活，而ADH刺激两者。这一新的假设认为，ADH激活ENaC的作用从主要影响血浆钠转变为促进尿液浓度，从而通过三个具体目标进行测试：(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对全身钠和水平衡的贡献；(3)了解ADH刺激的ENaC对低钠和高钠血症病理状态的贡献。完成这些目标将提供对调节肾脏钠和水排泄以及全身钠和水平衡的基本生理过程的机械性洞察。

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.