Regulation of Renal Na+ Excretion by Antidiuretic Hormone

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. PUBLIC HEALTH RELEVANCE: Recent studies from our laboratory find that the activity of ENaC in the distal nephron, surprisingly, is sustained high by ADH in states of water and electrolyte imbalance associated with suppressed aldosterone levels. I seek here to determine whether this ENaC activity is causal or compensatory to the hyponatremia resulting from elevated ADH during syndrome of inappropriate ADH secretion (SIADH), and whether it is compensatory or maladaptive to the hypernatremia resulting from prolonged consumption of hypertonic saline, which also is associated with elevated ADH levels. Testing the contribution of ADH-activated ENaC to electrolyte and water balance under these contrasting conditions will elaborate a long-standing riddle about the biological limitations in mammals that can cause disease when the need to protect plasma sodium and osmolality are in competition.