Vasopressin and Aquaporin 2 in Clinical Disorders of Water Homeostasis

Abstract

The cloning of the V2 vasopressin receptor was a major advance in understanding the mechanisms involved in regulation of solute-free water excretion by arginine vasopressin (AVP) (1). Subsequently, mutations of the V2 receptor gene were found to account for approximately 85% of cases of congenital nephrogenic diabetes insipidus (2). The mechanisms whereby AVP activates the V2 receptor on the basolateral membrane of the principal cells of the collecting duct and leads to increased water permeability of the apical membrane were, however, quite perplexing. The water transport across the bilipid apical membrane of the principal cells was too fast to be due to diffusion alone. Thus, the shuttle hypothesis was proposed whereby theoretical water channels would be moved from the cytoplasm to the apical membrane of the principal cells by AVP (3). The discovery of the first water channel, aquaporin 1 (AQP1), by Agre and associates led to great excitement in the biomedical community and the awarding of the Nobel Prize in Chemistry in 2003 to Peter Agre (4). Subsequently, aquaporin 2 (AQP2) was identified by Sasaki et al. in the principal cells of the collecting duct (5). Further investigations have demonstrated that AVP is the major regulator of the AQP2 water channels (6). Activation of the V2 receptor on the principal cells of the collecting duct by AVP is associated with a cascade of events involving adenylyl cyclase-mediated cyclic AMP (Figure 1) (7) which leads to both short term and long term regulation of AQP2 (8,9). The short term regulation of AVP involves shuttling the AQP2 containing vesicles from the cytoplasm to the apical membrane. With suppression of vasopressin these apical AQP2 water channels then undergo endocytosis into the cytoplasm (3). The 5' flanking region of the AQP2 gene has a cyclic AMP response element which is involved in the long term upregulation of AQP2 protein expression by AVP (9).The discovery of non-peptide antagonists to the V2 receptor have added yet another important dimension to the understanding of total body water homeostasis (10). These V2 receptor antagonists are agents that specifically block the action of AVP in humans. The several V2 receptor antagonists presently involved in clinical studies are shown in Table 1 (11). In contrast to diuretics, which enhance urine water and electrolyte excretion, the V2 receptor antagonists increase electrolyte-free water excretion.A relative excess of total body water to cation concentration leads to hyponatremia in many clinical circumstances. In fact, hyponatremia is the most frequent electrolyte disturbance in hospitalized patients (12). V2 receptor antagonists have substantial clinical implications, since the majority of the hyponatremic states are due to the non-osmotic release of AVP (13). These V2 receptor antagonists have also been important vehicles to understand several waterPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

Osmotic Homeostasis

“…Vasopressin is a potent endogenous peptide influencing a wide array of biologic functions, including regulation of water balance, BP, platelet function, and thermoregulation (47)(48)(49). It is synthesized as a prohormone in the magnocellular cell bodies of the paraventricular and supraoptic nuclei of the posterior hypothalamus, and by binding to the carrier protein neurohypophysin, it is transported along the supraoptic hypophyseal tract to the axonal terminals of magnocellular neurons in the posterior pituitary.…”

Plasma osmolality predicts mortality in patients with heart failure with reduced ejection fraction

“…Urea also plays a basic and direct role in the fluid and sodium homeostasis, which is regulated by the neurohormonal system [24]. Increased BUN levels may indicate adrenergic activation, activation of the renin-angiotensin-aldosterone system, and increased vasopressin levels [25][26][27]. Although high BUN…”

Localization of Canine, Feline, and Mouse Renal Membrane Proteins

“…32,35,39 Once AQP2 has relocated to the apical plasma membrane, water can be reabsorbed through the water channel, concentrating urine. 32,35,39 Conversely, in the absence of vasopressin, AQP2 is endocytosed back into the cytoplasm, and water is excreted in the urine. 32,35,39 AQP1 and AQP2 have been studied extensively in human medicine, primarily relying on rat and mice models.…”