European Journal of Clinical Nutrition (2003) 57, Suppl 2, S39–S46 & 2003 Nature Publishing Group All rights reserved 0954-3007/03 $25.00 www.nature.com/ejcn ORIGINAL COMMUNICATION Mild dehydration, vasopressin and the kidney: animal and human studies N Bouby1* and S Fernandes1 1INSERM U 367, Paris, France Water balance depends essentially on fluid intake and urine excretion. Mild dehydration and the consequent hypertonicity of the extracellular fluid induce an increase in vasopressin secretion, thus stimulating urine concentrating processes and the feeling of thirst. The osmotic threshold for the release of vasopressin is lower than that for thirst and also shows appreciable individual variation. Sustained high levels of vasopressin and low hydration induce morphological and functional changes in the kidney. However, they could also be risk factors in several renal disorders, such as chronic renal failure, diabetic nephropathy and salt- sensitive hypertension. European Journal of Clinical Nutrition (2003) 57, Suppl 2, S39–S46. doi:10.1038/sj.ejcn.1601900 Keywords: water intake; dehydration; vasopressin; kidney Introduction temperature, angiotensin (Berl & Robertson, 2000). Increase Water balance depends essentially on two parameters: thirst in plasma osmolality is also the main stimulus for thirst. that influences input, and urine excretion that determines However, the desire to drink is triggered by an osmotic level output. In humans and most other mammals, the rate at considerably higher than that leading to the secretion of which the kidneys excrete free water is regulated primarily vasopressin (Robertson, 1984). AVP release begins at an by antidiuretic hormone or vasopressin. Vasopressin is the average plasma osmolality of about 280 mosm/kg H2O, first hormone to be secreted during dehydration. Changes in whereas thirst is not perceived until plasma osmolality the plasma level of other hormones are also observed reaches about 290 mosm/kg H2O. Thus, during normal living (increases in atrial natriuretic peptide and catecholamines, conditions, vasopressin is constantly present in the blood, fall in aldosterone), but they occur later and in response to whereas the perception of thirst is intermittent. The severe dehydration. sensitivity and threshold of the osmoregulatory systems Vasopressin is synthesized in specific neurons in the show wide inter-individual variability in both humans and supraoptic and paraventricular nuclei and stored in the rats (Zerbe et al, 1991; Bankir, 2001). These individual neurohypophysis. Under physiological conditions, the most differences are constant over prolonged periods and appear important stimulus of vasopressin secretion is the effective to be determined mainly by genetic factors (Zerbe et al, osmotic pressure of the plasma. Increase in plasma osmol- 1991). Since the osmoregulatory mechanisms are not equally ality is related physiologically to dehydration and a change sensitive in all healthy individuals, one could expect some in water balance, and can be induced experimentally by subjects to tend to be continuously in a state of slight infusing hypertonic solutions. Vasopressin secretion is also dehydration, and to have a high level of vasopressin to influenced by hemodynamic factors (reduction of blood compensate. pressure or blood volume), emetic factors (nausea, drugs Three vasopressin receptors have been identified and such as nicotine or morphine) and factors such as stress, cloned, V2 with cAMP as second messenger, and V1a and V1b with calcium as second messenger. The antidiuretic *Correspondence: N Bouby, INSERM U 367, 17 rue du Fer a` Moulin, 75005 action of vasopressin depends mainly on V2 receptor- Paris, France. E-mail: [email protected] mediated effects in the renal collecting duct. This minire- Guarantor: N Bouby view addresses the functional impact on the kidney of mild Contributors: NB was primarily responsible for the writing of the dehydration and activation of V2 receptor of vasopressin, in paper. SF took part in the acquisition of some experimental data and preparation of the paper. health and disease. Animal and human studies N Bouby and S Fernandes S40 Renal consequences of a high level of vasopressin a in a healthy subject 2.0 In healthy subjects, high vasopressin levels induce morpho- Cortex Medulla logical and functional changes in the kidney resulting in greater urine-concentrating activity. Urine concentration 1.5 depends on the water permeability of the collecting duct and on the presence of a corticomedullary osmotic gradient. 1.0 Vasopressin contributes to the urine-concentrating mechan- ism by influencing the permeability to water and urea, and AQP2 mRNA sodium transport in the distal part of the tubule. 0.5 At least six types of water channel proteins (aquaporins, AQP) are known to be expressed in the kidney. Among these, AQP2, localized in the luminal membrane of the principal 0 cells of the collecting duct, is the chief target for the short- term regulation of the collecting duct permeability by b vasopressin. AQP2, and also AQP3 and AQP4 (basolateral 7 ) n water channels of the collecting duct), are regulated via the i 6 m / long-term effects of chronic dehydration that change the g 5 n total abundance of these three channels in collecting duct ( e cells (Figure 1a) (Yamamoto et al, 1995; Ishibashi et al, 1997; t 4 a Murillo-Carretero et al, 1999; Kwon et al, 2001) (the effect on r 2 3 AQP3 is only partially mediated by stimulating vasopressin P Q 2 V2 receptors). As urinary AQP2 excretion is very low A - r=0.67, p<0.006 compared to the total AQP2 in the kidney (E3%), it may u 1 ∆ not reflect intrarenal changes in the protein. Nevertheless, a 0 positive correlation has been found recently between the 0 12345 6 maximum changes in the urinary excretion of AQP2 and the ∆ AVP (pmol/l) maximum changes in plasma vasopressin in healthy subjects Figure 1 Influence of water intake on the expression of aquaporin et al (Pedersen , 2001) (Figure 1b). 2. (a) Relative mRNA levels of AQP2 in the renal cortex and medulla The driving force behind the water flux and urine of rats maintained for 2.5 days on different water intake levels concentration is an osmotic corticomedullary gradient that resulting in urine osmolality values of 906, 3140 and 380 mosm/kg is built-up as a result of the reabsorption of sodium in the H2O in control (open bars), thirsty (solid bars) and highly hydrated (hatched bars) rats, respectively, adapted from Murillo-Carretero et al thick ascending limb and the accumulation of urea in the (1999). (b) Correlation between the maximum changes in plasma inner medulla. An increase in the abundance of the vasopressin (DAVP) and maximum changes in urinary AQP2 (Du- bumetamide-sensitive Na–K–2Cl cotransporter protein in AQP2) rate in healthy subject during water deprivation for 24 h, the thick ascending limb has been observed in the rat kidney reproduced from Pedersen et al (2001). in response to either chronic water restriction or chronic infusion of a vasopressin V2 receptor agonist (Kim et al, 1999). However, this direct effect of vasopressin on the In addition to its effects on water and urea permeability, reabsorption of sodium in the thick ascending limb occurs vasopressin also improves urine concentration by stimulat- only in some rodents. In humans, this nephron segment is ing the reabsorption of sodium from the connecting tubule devoid of vasopressin-sensitive adenylate cyclase activity and the collecting duct, which promotes additional iso- (Morel et al, 1987). Facilitated urea transporters are respon- osmotic water reabsorption. This effect involves the activa- sible for accumulation of urea in the renal inner medulla. tion of the amiloride-sensitive epithelial sodium channel Three major urea transporters have been cloned and located (ENaC). It has been shown recently that vasopressin not only in different structures of the kidney: UT-A1, UT-A2 and UT- has an acute impact on ENaC-dependent sodium transport B1 (Figure 2a). In rats and human beings, UT-A1 is located in (Tomita et al, 1985; Verrey, 1994; Blot-Chabaud et al, 1996; the terminal part of the inner medullary collecting duct and Djelidi et al, 1997) but also has a delayed effect on the accounts for the vasopressin-dependent increase in the urea expression of b and gENaC subunits, in the kidney, by permeability of this segment (Knepper & Star, 1990; activating the V2 receptors (Ecelbarger et al, 2000; Nicco et al, Bagnasco et al, 2001). Like the aquaporins, chronic vaso- 2001) (Figure 3). This effect is accompanied by a significant pressin infusion affects not only UT-A1 but also another urea increase in sodium and water transport (Nicco et al, 2001) transporter, UT-A2, located in the thin descending limb of (Figure 4), suggesting associated changes in functional ENaC Henle’s loop (Bankir & Trinh-Trang-Tan, 2000) (Figure 2b). membrane proteins. Interestingly, an increase in the mRNA This effect on UT-A2 must be indirect because there are no expression of b and gENaC subunits has also been observed vasopressin receptors in the thin descending limb. in the lung of rats with either chronic water restriction or European Journal of Clinical Nutrition Animal and human studies N Bouby and S Fernandes S41 a a *** 4 3 2 ** ENaC/ GAPDH 1 A 0 α β γ b 2.5 ** 2.0 *** *** * 1.5 b 1.0 Urine osmolality (mosm/kg H20) ENaC/ GAPDH 440 918 2800 3300 0.5 0.0 α β γ UT-A2 IS Figure 3 Influence of vasopressin on the mRNA level of the three subunits (a, b, g) of the epithelial sodium channel (ENaC) in the renal cortex. (a) Brattleboro rats chronically treated with a V2 agonist of vasopressin (n¼6, solid bars) or untreated (n¼5, open bars). (b) Sprague–Dawley rats chronically treated with a V2 agonist of UT-A1 vasopressin (n¼6, solid bars), with restricted drinking water (n¼6, UT-A2 hatched bars) or untreated (n¼6, open bars).