Pathophysiological roles of arginine vasopressin and aquaporin‐2 in impaired water excretion (2003)

Impaired water excretion occurs in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), adrenal insufficiency, congestive heart failure and liver cirrhosis with ascites (Bartter & Schwartz, 1967; Schrier, 1988a,b). In these clinical settings, there is hyponatraemia to various extents. Nonsuppressible release of arginine vasopressin (AVP, ADH) is found despite hypoosmolality, which should suppress AVP release to undetectable levels. Reversal of hyponatraemia by specific antagonists of AVP provides conclusive evidence for the role of AVP in pathological states of water retention. In response to AVP, concentrated urine is produced by water reabsorption across renal collecting ducts (Ishikawa, 1993; Knepper & Rector, 1995). The aquaporin-2 (AQP-2) water channel was discovered by Sasaki and colleagues (Fushimi et al., 1993), and is an AVP-regulated water channel in collecting duct cells. There are two regulatory systems: short-term and long-term regulation. The upregulation of kidney AQP-2 expression is closely related to the nonsuppressible release of AVP in the experimental models of SIADH, liver cirrhosis, congestive heart failure, and adrenal insufficiency (Asahina et al., 1995; Fujita et al., 1995; Nielsen et al., 1997; Xu et al., 1997; Saito et al., 2000). Kidney AQP-2 expression has been quantitatively estimated by urinary excretion of AQP-2 (Kanno et al., 1995; Rai et al., 1997). Approximately 3% of AQP-2 in the collecting duct cells is excreted into urine (Rai et al., 1997), and urinary excretion of AQP-2 positively correlates with plasma AVP levels in normal subjects (Saito et al., 1997c). In this review, we focus on the close association of kidney AQP-2 expression with exaggerated release of AVP in pathological states of impaired water excretion. Furthermore, the diagnostic value of urinary excretion of AQP-2 in disorders of water metabolism dependent on AVP is discussed. AVP is a peptide hormone of the posterior pituitary gland that is synthesized in both magnocellular and parvocellular neurosecretory neurones of the hypothalamus (Arnaud et al., 1974; Brimble & Dyball, 1977; Poulain & Wakerley, 1982). Cell bodies of these neurones reside primarily in the supraoptic nuclei (SON) and the paraventricular nuclei (PVN) (Rhodes et al., 1981). The major projection of magnocellular neurosecretory neurones is to the posterior pituitary gland. In the posterior pituitary gland a large amount of AVP, the associated neurophysin (NPII) and glycopeptide are stored in neurosecretory granules. The magnocellular neurones in the SON and PVN respond to both osmotic and nonosmotic stimulation and are involved in the control of body water content and blood pressure. The axon terminals of parvocellular neurones, which originate in the PVN, reach the zona externa of the median eminence of the hypothalamus (Parry & Livett, 1973). AVP is secreted from these axons into the pituitary portal circulation, and stimulates ACTH secretion via AVP V1b receptor activation (Rabadan-Diehl et al., 1997). AVP neurones also project to certain areas of the central nervous system, including the brainstem and spinal cord, where AVP acts a neurotransmitter, possibly involved in a variety of functions (Rivier & Vale, 1983; Vale et al., 1983; Knepel et al., 1984). Physiological studies suggest that there is independent control of AVP secretion between magnocellular and parvocellular neurones. Osmotic and nonosmotic stimulations are the two major factors that control AVP release. Osmoreceptors reside in the anteroventral third ventricle (AV3V) region of the hypothalamus, particularly in the organum vasculosum of the lamina terminalis (OVLT) (Thrasher et al., 1982; Thrasher & Keil, 1987; Osaka et al., 1988), and are very sensitive to changes in plasma osmolality (Posm). This region is located outside the blood–brain barrier. There are neural inputs from the osmoreceptors to the PVN and SON, probably mediated via a cholinergic pathway (Sladek & Joynt, 1979). It is evident that other pathways from the brainstem to the magnocellular neurosecretory neurones of the SON and PVN are present (Harris et al., 1975; Day & Sibbald, 1988). These pathways are based on catecholaminergic neurones (Head et al., 1987). Afferent fibres from arterial baroreceptors terminate in the nucleus of the tractus solitarius of the dorsomedial medulla oblongata (Sved et al., 1985; Catelli et al., 1987). Chemical inhibition and lesions of this nucleus increase plasma AVP levels, suggesting an effect attributable to the interruption of tonic baroreceptor inhibition of AVP release (Blessing & Willoughby, 1985; Head et al., 1987). A series of studies with interruption of the glossopharyngeal and vagal pathways from arterial baroreceptors also demonstrated potent nonosmotic AVP stimulation (Schrier & Berl, 1972, 1973; Schrier et al., 1972). The A1 adrenergic cell group of the ventrolateral medulla is suggested to be involved in the afferent pathway from the nucleus of the tractus solitarius to neurosecretory AVP cells of the SON and PVN. AVP is generated from a precursor form of prepro AVP, which is encoded by the AVP gene on chromosome 20 (Simpson, 1988). The AVP gene has three exons. Exon A encodes the signal peptide, AVP and the N-terminal region of NPII. Exon B encodes the highly conserved central part of NPII. Exon C encodes the C-terminal region of NPII, and the glycoprotein domain (Schmale et al., 1983). The hormone precursor, prepro AVP, contains signal peptide, AVP, NPII and glycoprotein domains. This structural organization of prepro AVP and the AVP gene is conserved among various species. Pro AVP is generated by removing the signal peptide from prepro AVP and by adding a carbohydrate chain to the glycoprotein domain. Additional posttranslational processing of prepro AVP, which yields AVP, NPII and glycoprotein, occurs within neurosecretory granules during their transport to axon terminals in the posterior pituitary. AVP, NPII and the glycoprotein are stored in neurosecretory granules in axon terminals of the posterior pituitary, and are released into the bloodstream in response to osmotic or nonosmotic stimulation. The functional properties of NPII and glycoprotein are not completely understood, but intact NPII is at least necessary for the processing of AVP in the endoplasmic reticulum (Kim et al., 1997; Kim & Schrier, 1998). The 5′-flanking region of the AVP gene is thought to contain several putative regulatory elements. Mohr and Richter (1990) showed the sequences of glucocorticoid responsive element (GRE) and cyclic AMP (cAMP) response element (CRE) in the promoter region along with activator protein-2 (AP-2) binding sites. Glucocorticoid hormones suppressed AVP mRNA expression in the parvocellular neurones of the PVN, and dexamethasone abolished its increased expression (Davis et al., 1986). In addition, in vivo and in vitro studies have shown that cAMP induces the expression of AVP mRNA, and might be involved in osmotically stimulated AVP gene expression (Verbeeck et al., 1990). A progressive increase in mRNA has been found in the magnocellular neurosecretory neurones of PVN and SON in rats receiving hypertonic saline or in dehydrated rats (Lightman & Young, 1987). Mature mRNA is produced from precursor RNA by splicing to remove the intron regions and adding the 7-methylguanine cap structure in the 5′-flanking region and a polyadenylate [poly(A)] tail in the 3′-flanking region. Only 2 h of water deprivation is necessary to induce an increased length of the poly(A) tail of the AVP mRNA, an effect that occurs prior to any detectable change in Posm. However, the AVP mRNA accumulation occurred after dehydration for 2 days (Carter & Murphy, 1991). Thus, at least two modes of mRNA regulation might be involved in AVP gene expression. The expression of c-fos and carboxypeptidase mRNAs accompanies the osmotic stimulation of AVP mRNA expression. In rats, intraperitoneal administration of hypertonic saline produced the protooncogene c-fos mRNA expression in the AVP-producing nuclei and the anterior periventricular region of the hypothalamus (Hamamura et al., 1992). Carboxypeptidase H is involved in posttranslational processing of neuropeptide precursors. Osmotic stimulation increased the expression of carboxypeptidase H mRNA in AVP-producing neurones, as well as AVP mRNA expression (Bondy et al., 1989). Schema of normal regulation of water balance by AVP. There is a close correlation between Posm and plasma AVP levels in healthy subjects and in subjects with various states of hydration (Robertson et al., 1973; Schrier et al., 1979). Linear regression analysis has yielded the osmotic threshold for AVP secretion and the sensitivity of osmoreceptors. The osmotic threshold for AVP secretion is the point of the interception on the horizontal axis, that is approximately 280 mmol/kg. Several factors potentially affect the osmotic threshold (Dunn et al., 1973). There seems likely to be a species difference in osmotic threshold for AVP secretion; the osmotic threshold ranges from 285 to 292 mmol/kg in the rat, dog and monkey, values higher than the 280 mmol/kg threshold in humans (Dunn et al., 1973; Robertson et al., 1973). Posm decreases by 8–10 mmol/kg during pregnancy, and this decrease is followed by a decrement in the osmotic threshold for AVP release (Davison et al., 1988). The osmotic threshold is also influenced by nonosmotic stimuli (Robertson et al., 1977). Decreases in circulatory blood volume and blood pressure enhance the secretion of AVP by the osmotic stimulus, which shifts (increases) the osmotic threshold to the left in the absence of any change in the sensitivity (Dunn et al., 1973). The sensitivity of osmoreceptors is rather extraordinary. A 1-mmol/kg change in Posm will alter AVP release; this sensitivity, however, is influenced by the nature of the solute. Increases in Posm produced by sodium, sucrose and mannitol exert comparable osmotic effects, but this is not the case with urea or glucose (McKinley et al., 1978; Ishikawa et al., 1980). Other factors, such as the rate of change in Posm, age and drinking behaviour, can also affect osmotic sensitivity. Decreases in arterial blood pressure and circulating blood volume are potent nonosmotic stimuli for AVP secretion, mediated via the high-pressure and low-pressure (left atrial) baroreceptors. It has been generally accepted that a decrement in blood pressure or blood volume of the order of 8–10% is necessary to stimulate AVP secretion. Baylis (1983) demonstrated that the relationships between plasma AVP concentrations and the percentage fall in mean arterial blood pressure is exponential. Several factors, including low cardiac output, left atrial distention, atrial tachycardia, nicotine and hypoxia, are also nonosmotic stimulants for AVP release (Schrier et al., 1979). It is of value to note the separate osmotic and nonosmotic control of AVP release. Electrophysiological studies verified that the osmotic and nonosmotic pathways independently enter the same magnocellular neurosecretory neurones of the PVN and SON (Kannan & Yagi, 1978). 'Reset' osmostat suggests an intrinsic alteration in osmoreceptor cells so that a lower or a higher level of Posm is sensed as normal (Robertson et al., 1977). However, many clinical disturbances of Posm can be interpreted by competitive inputs of baroreceptor and osmoreceptor pathways into the same population of neurosecretory cells, independent of any intrinsic alteration in osmoreceptor sensitivity. In hyponatraemic patients with SIADH, cardiac failure and liver cirrhosis with ascites, the nonosmotic release of AVP might override the effect of hypoosmolality to suppress AVP release. Clinical and laboratory experiments have demonstrated that AVP plays a crucial role in impaired water excretion in pathological states of euvolaemic and hypervolaemic hyponatraemia (Schrier, 1988a,b). Euvolaemic hyponatraemia includes SIADH, hypopituitarism and glucocorticoid deficiency, and hypervolaemic hyponatraemia is found in oedematous diseases, including congestive heart failure, liver cirrhosis with ascites and nephrotic syndrome. The causes of nonsuppressible release of AVP are discussed below. The diagnostic criteria of SIADH were initially described by Bartter and Schwartz (1967). The criteria include hyponatraemia, hypoosmolality, hypertonic urine with neither dehydration nor oedema, and no dysfunction of kidney and adrenal gland. There are two sources of AVP in SIADH, including either ectopic production of AVP in lung cancer, pancreatic cancer, duodenal cancer and others, or increased central secretion of AVP from the posterior pituitary gland due to disorders of the central nervous system and lungs, or drugs. Radioimmunoassay techniques demonstrated the elevation of plasma AVP concentration in patients with SIADH despite hypoosmolality, and AVP secretion was not suppressed by an acute oral water load. Normal values of plasma AVP are observed frequently in SIADH; these plasma AVP concentrations are, however, increased with respective to the low Posm (Saito et al., 1997a). These issues have been dealt with in other reviews. As described initially by Verbalis and Drutarosky (1988), model animals of SIADH were made by the subcutaneous administration of the V2 agonist 1-deamino-8-D-AVP (dDAVP) by osmotic minipumps, and offering a liquid diet. In this model a serum sodium concentration less than 120 mmol/l occurred in association with a concentrated urine throughout the 14-day observation period (Fujisawa et al., 1993). The oral administration of the nonpeptide V2 receptor antagonist OPC-31260 was started on day 7 and continued once a day during the rest of experiment. This manoeuvre promptly normalized serum sodium levels in 12 h in association with an increase in urine volume and a decrease in urinary osmolality. The normalization of serum sodium concentration was maintained during the rest of the experimental period (Fujisawa et al., 1993). Similar results were obtained in experimental SIADH animals with the peptide AVP V2 receptor antagonists d(CH2)5Tyr(Et)VAVP or d(CH2)5DTyr(Et)VAVP (Laszolo et al., 1984; Kinter et al., 1986). In these other studies, the SIADH model was made by subcutaneous injection of pitressin or dDAVP, and the V2 AVP antagonists were administered intravenously or intraperitoneally. The in vivo use of AVP V2 receptor antagonists directly verifies the AVP dependency of impaired water excretion, because both peptide and nonpeptide antagonists are known to specifically antagonize the V2 receptor binding of AVP (Sawyer et al., 1981; Yamamura et al., 1992; Serradeil-Le Gal et al., 1996). These results indicate that the dilutional hyponatraemia in the rats with the experimental model SIADH can be reversed by the AVP V2 receptor antagonists. The efficacy of the nonpeptide AVP V2 receptor antagonist OPC-31260 has also been demonstrated in patients with SIADH (Saito et al., 1997a). A single intravenous injection of OPC-31260 increased urine volume, decreased urinary osmolality (Uosm) and increased serum sodium levels by approximately 3 mmol/l during the 4-h observation period (Fig. 2). Following the initial study, chronic oral administration of OPC-31260 was shown to be very effective in the patients with SIADH (unpublished observation). Alteration in urine volume (a) and Uosm (b) after intravenous administration of the nonpeptide AVP antagonist OPC-31260 in patients with SIADH. Control (▪), 0·1 mg/kg OPC-31260 (○), 0·25 mg/kg OPC-31260 (□), and 0·5 mg/kg OPC-31260 (•). * P < 0·05 and ** P < 0·01 vs. the respective values at the first urine collection. (Data from Saito et al., 1997a.) Hyponatraemia in hypopituitarism and glucocorticoid deficiency is closely related to the nonsuppressible release of AVP despite hypoosmolality (Slessor, 1951; Amhed et al., 1967; Ishikawa & Schrier, 1982; Pyo et al., 1993). Hypothalamic AVP mRNA expression was increased in adrenalectomized rats (Hermann, 1995; Ma & Aguilera, 1999). In glucocorticoid-deficient rats impaired water excretion was demonstrated by an acute water load (Saito et al., 2000). The administration of peptide and nonpeptide AVP V2 receptor antagonists totally normalized renal water excretion (Pyo et al., 1993; Saito et al., 2000). Plasma AVP levels remained in the normal ranges in the glucocorticoid-deficient rats despite hypoosmolality, which should suppress plasma AVP to an undetectable level. There were no alterations in Kd and Bmax in [3H]AVP receptor binding between the glucocorticoid-deficient and the control rats (Saito et al., 2000). Also, no change in the expression of AVP V2 receptor mRNA was found. Therefore, no downregulation of AVP receptor binding was found in glucocorticoid deficiency under this condition of nonsuppressible AVP release. Intrarenal factors could also participate in the impairment of water excretion in glucocorticoid deficiency; this is discussed later. The replacement of hydrocortisone in glucocorticoid-deficient rats normalized renal water excretion, plasma AVP levels and serum sodium concentration. Thus, glucocorticoid deficiency per se appears to be the primary factor for the exaggerated release of AVP from posterior pituitary gland with hypopituitarism. Liver cirrhosis. The pathogenesis of the nonosmotic stimulation of AVP is similar in oedematous disorders. Anderson et al. (1976) demonstrated that removal of the endogenous source of AVP by acute hypophysectomy improved renal water excretion in glucocorticoid-replaced dogs with acute portal vein constriction. However, a residual factor in the impaired water excretion persisted, thus implicating intrarenal factors. It has also been shown that plasma AVP levels are elevated in cirrhotic rats and humans, and AVP secretion was not sufficiently suppressed by an acute water load (Linas et al., 1981; Bichet et al., 1982a, 1983; Reznick et al., 1983; Tsuboi et al., 1994). Additionally, the expression of AVP mRNA in the hypothalamus was significantly increased in cirrhotic rats (Kim et al., 1993). Bichet et al. (1982a) further studied the mechanisms of impaired water excretion in patients with liver cirrhosis. Decompensated cirrhotic patients exhibited hyponatraemia, ascites and peripheral oedema. There was a significant increase in basal concentration of plasma AVP in the decompensated cirrhotic patients compared to compensated cirrhotic patients without ascites. An acute water load maximally suppressed plasma AVP to below 0·5 pmol/l in the compensated cirrhotic patients, whereas the decompensated cirrhotic patients did not suppress plasma AVP and their hyponatraemia persisted. Furthermore, activation of the renin–angiotensin–aldosterone system and the sympathetic nervous system was present in the cirrhotic patients, and the degree of activation correlated directly with the degree of water and sodium retention (Bichet et al., 1982b; Arroyo et al., 1983). Several mechanisms for the exaggerated secretion of AVP and other neurohumoral hormones in patients with liver cirrhosis have been proposed (Anderson et al., 1976; Linas et al., 1981; Bichet et al., 1982a,b, 1983; Arroyo et al., 1983; Reznick et al., 1983; Schrier, 1988b; Kim et al., 1993; Tsuboi et al., 1994). It is evident that V2 receptor antagonists reversed the impairment in renal water excretion in the experimental model of cirrhotic rats (Fig. 3) (Claria et al., 1989; Tsuboi et al., 1994). Greater activation of the sympathetic nervous system, the renin–angiotensin–aldosterone system and the nonosmotic release of AVP in decompensated compared with compensated cirrhotic patients suggests that as cirrhosis progresses there is more evidence of arterial underfilling with neurohumoral stimulation. Effect of the nonpeptide AVP antagonist OPC-31260 on renal water excretion after an acute water load (30 ml/kg body weight) in rats with CCl 4 -induced liver cirrhosis (LC). (a) Percent excretion of water load. (b) Minimal Uosm. (Data from Tsuboi et al., 1994.) Peripheral arterial vasodilatation, primarily in the splanchinic vascular bed, has been proposed to account for the neurohumoral stimulation and the initiation of water and sodium retention in patients with cirrhosis (Gines et al., 1996). Nitric oxide contributes to the vasodilatation, in addition to the anatomical shunting (Martin et al., 1998). The peripheral arterial vasodilatation in cirrhosis produces renal sodium and water retention, and leads to an increase in total blood volume. However, this volume expansion is not sufficient to refill the enlarged arterial vascular compartment. A reduction in 'effective arterial blood volume' is closely related to the elevation of plasma AVP, renin, aldosterone and (Schrier, 1988a,b). The arterial underfilling that occurs as a of the arterial vasodilatation plays a crucial role in the secretion of these hormones in cirrhotic patients (Bichet et al., 1983). Nitric oxide appears to be a of the vasodilatation in cirrhosis, and an inhibition of oxide for 7 days the circulation, and plasma AVP, and aldosterone levels and renal water and sodium retention in experimental cirrhosis (Martin et al., 1998). Nonsuppressible AVP release in cirrhosis water reabsorption in collecting duct cells, and results in impaired water excretion. In the circulation, elevated plasma AVP might to the of arterial pressure by stimulation of the AVP receptor (Claria et al., 1991). water induces an increase in central blood volume et al., and this manoeuvre has been in patients with liver cirrhosis to the and renal water excretion were (Bichet et al., 1983). water suppressed plasma AVP aldosterone and in the decompensated cirrhotic patients with ascites, in an increase in renal sodium and water excretion. showed that water increased cardiac output, atrial pressure and and decreased vascular et al., 1986). It should be however, that water but did not renal water and sodium excretion in cirrhotic patients with ascites. There are at least two for the in renal sodium and water excretion. any that might be by increased pressure not be to to a by water & mean arterial pressure did not despite the in cardiac during water because of a further decrease in vascular in these cirrhotic patients (Bichet et al., 1983). the arterial vasodilatation, et al. the effect of during water on renal water and sodium excretion in cirrhotic This manoeuvre normalized renal water and sodium excretion in the decompensated cirrhotic patients compared to control studies in the same were observed in atrial pressure and cardiac output, but mean arterial pressure in association with a increase in vascular These results the peripheral arterial vasodilatation of water and sodium retention in cirrhosis. heart In several models of and cardiac failure and in congestive heart failure in humans, has been demonstrated that plasma AVP, aldosterone and are increased significantly et al., 1981; & 1982; et al., 1985; et al., 1984; Bichet et al., Ishikawa et al., 1986). nonosmotic release of AVP was closely associated with increased expression of AVP mRNA in the hypothalamus of rats with congestive heart failure to (Kim et al., 1990). The administration of AVP V2 receptor antagonists the of AVP in the impairment in renal water excretion in rats with heart failure et al., et al., 1994). The peptide V2 receptor antagonist reversed the in water excretion in the model of cardiac failure to of the et al., 1986). nonpeptide antagonists of the AVP V2 receptor Xu et al. and et al. have shown that these nonpeptide antagonists improved water excretion in heart failure in rats with of and humans with congestive heart failure, Bichet et al. the effect of the and the in the in water retention in patients with and congestive heart The administration of these cardiac and increased cardiac output, improved renal water excretion and suppressed plasma AVP in response to an acute water load. The that a decrease in volume and cardiac output, as sensed by arterial appears to be the primary for the nonosmotic release of AVP in cardiac failure, an effect that can be reversed by cardiac In impaired water excretion occurs in patients with SIADH, adrenal insufficiency, liver cirrhosis with ascites and congestive heart These patients are into euvolaemic or hypervolaemic Nonsuppressible release of AVP is found despite hypoosmolality, which should suppress AVP release to undetectable levels. The exaggerated release of AVP is stimulated by a decrease in 'effective circulatory blood volume' in liver cirrhosis with ascites and congestive heart Reversal of hyponatraemia by the AVP V2 receptor antagonists provides conclusive evidence for the role of AVP in pathological states of impaired water excretion, and a use of the AVP receptor antagonists per AVP on the of renal collecting duct cells are to the to the activation of (Ishikawa, 1993; Knepper & Rector, 1995). These are as V2 et al. and et al. independently AVP V2 in and The V2 receptor encodes and has in its which is of with AVP leads to a change in the receptor and replacement of with in the of This the activation of to promptly cyclic AMP is the that A and is by of the of AVP to the AQP-2 water of the collecting This leads to increased AQP-2 mRNA expression and of AQP-2 water from the of to the plasma Sasaki and group (Fushimi et al., 1993; Sasaki et al., the of and a chain This is in the of the major intrinsic et al., 1984; & 1996). and AQP-2 are with with and with & 1991). These water have putative an and a conserved of the AQP-2 gene its to chromosome analysis showed that AQP-2 mRNA is in the along the that the expression of AQP-2 mRNA is to the collecting duct from the collecting duct to the collecting duct studies an a peptide to the of AQP-2 showed that AQP-2 is in the cells of the collecting The AQP-2 was in the and regions et al., 1993). demonstrated that AQP-2 in in the region in the condition et al., 1993). the administration of AVP or dehydration produced of AQP-2 from the to the plasma (Fushimi et al., 1993; Nielsen et al., 1995; et al., et al., 1995; et al., 1995). An reduction in plasma AVP concentrations or the AVP V2 receptor antagonist causes of AQP-2 into the et al., Saito et al., et al., 1998). This observation AQP-2 as the AVP-regulated water channel and