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Na+和水调节的机制。低钠血症是一种常见的电解质异常，具有潜在的高发病率和死亡率，本研究旨在探讨抗利尿激素（ADH）在低钠血症期间调节肾Na+的机制。由于肾脏对Na+和水排泄的差异控制的基本机制尚不清楚，目前治疗低钠血症的方法并不完全有效。血清Na+是通过稳态机制维持的，该机制涉及肾脏的自主水和Na+重吸收，分别由ADH和肾素-血管紧张素-醛固酮（RAAS）系统调节。最近的研究结果表明，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+和水排泄作用的药理学工具，这使低钠血症的治疗复杂化。血浆Na+和渗透压在远端肾元中通过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，增加远端肾元的水渗透性，并产生轴向皮质髓质高渗梯度，从这一段吸收水分。在这方面，ADH是抗脱水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再吸收的Na+有助于尿液浓度微调期间的高渗透梯度，这使得ENaC在这种意义上的激活也具有抗水合作用。然而，ENaC对减少自由水排泄的贡献是模糊的，似乎违反直觉。例如，如果adh激活的ENaC有助于浓缩尿液，那么它也一定有助于低钠血症。这似乎与ENaC对血浆Na+有积极作用的公认作用相矛盾。此外，在高钠血症状态下，ADH作为一种反馈反应升高，ENaC的激活如果对血浆Na+有积极影响，则会加剧这种情况，如果促进尿浓度，则会起到补偿作用。一个统一的范例，正如这里所测试的，

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.