The Role Of A Functional ADH Receptor Biology Essay

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A case was presented in which a child showed signs of oedema whose laboratory findings indicated a low serum sodium concentration (123mmol/litre), paired with a low serum osmolality (252mOsm/kg) and low antidiuretic hormone (ADH) levels (<10 ng/litre). These values were suppressed below the reference range. This was indicative of hyponatraemia, as well as euvolemia due to the low serum creatinine levels (<3 mg/litre) and normal aldosterone levels (10 ng/litre). The child suffered from mild systolic hypertension (128 mmHg). Despite low sodium and serum osmolality levels, the patient also demonstrated an inappropriately high urine sodium levels (35 mmol/litre) and low urine osmolality (284mOsm/kg). The presence of clinical signs of volume expansion coupled with the finding of elevated urinary sodium levels led to the hypothesis the presence of the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH). This clinical picture of SIADH raised the possibility of a receptor defect due to low ADH levels, which was confirmed by DNA sequencing of the ADH receptor. This led to a provisional diagnosis of the recently described Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIADH) or commonly known as Central Diabetes Insipidus. The patient was treated with fluid restriction, followed by administration of an osmotic agent (uea).


What is SIADH and what is the role of a functional ADH receptor?

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hyponatremia [1] and results from a failure of the negative feedback system that regulates the release and inhibition of ADH. The syndrome is defined by the decrease in serum osmolality, causing marked water retention and dilutional hyponatremia that results from inappropriate, continued secretion and/or action of antidiuretic hormone (ADH) despite normal or increased plasma volume, which results in impaired water excretion [1]. SIADH may occur as a transient condition, as in a stress situation, or as a chronic condition which are capable of triggering ADH release through action of the CNS. The suggested mechanism for SIADH in positive-pressure ventilation is activation of baroreceptors that respond to marked changes in intrathoracic pressure [1]. Disease and injury to the CNS can cause direct pressure on or direct involvement of the hypothalamic-posterior pituitary structures [2]. The manifestations of SIADH are those of dilutional hyponatremia in which urine osmolality is high and serum osmolality is low. Urine output decreases despite adequate or increased fluid intake [1].

The antidiuretic hormone (ADH) is formed in the supraoptic and paraventricular nuclei of the hypothalamus and is transported to the posterior lobe of the pituitary gland via the axons of the hormone producing neurons. ADH causes the incorporation, via V2-receptors and cAMP, of water channels into the luminal membrane and thus promotes water reabsorption in the distal tubules and in the collecting duct of the kidney. ADH also stimulates the tubular absorption of Na+ and urea. A high ADH concentration also leads to vasoconstriction (via V1-receptors and IP3). Stimuli for the release of ADH are extracellular hyperosmolarity (or cell shrinkage) and a decreased filling of the two atria.

ADH secretion is further stimulated by angiotensin II, dopamine, and some drugs or toxins. Increased atrial distension as well as GABA. ADH deficiency (A2) occurs if release is reduced, as in genetically determined central diabetes insipidus, in destruction of neurones, for example, by autoimmune disease, or other pituitary gland injury. However, in some situations ADH may fail to have an effect on the kidney, even if it is normally secreted, for example, because of defective water channels, or if the concentrating capacity of the kidney is otherwise impaired, as in K+ deficiency, Ca2+ excess, or inflammation of the renal medulla (renal diabetes insipidus). Decreased ADH release or effect results in the excretion of large amounts of poorly concentrated urine and hypertonic dehydration, leading to cell shrinkage. Patients will be forced to compensate for the renal loss of water by drinking large amounts (polydipsia). If the osmoreceptors in the hypothalamus are destroyed, ADH deficiency is accompanied by hypodipsia, and the hypertonic dehydration is especially marked. In psychogenic polydipsia. ADH release is inhibited because of the excess water, and thus, contrary to primary ADH deficiency, the result will be hypotonic hyperhydration.

What is the pathophysiology of NSIAD, leading to the mutation in the ADH receptor?

Two mechanisms that contribute directly to the regulation of body water and indirectly to the regulation of sodium are thirst and ADH. Thirst is primarily a regulator of water intake and ADH a regulator of water output. Both mechanisms respond to changes in extracellular osmolality and the effective circulating volume.

The reabsorption of water by the kidneys is regulated by ADH, also known as vasopressin. ADH is synthesized by cells in the supraoptic and paraventricular nuclei of the hypothalamus and then transported along a neural pathway (i.e., hypothalamohypophysial tract) to the posterior pituitary gland, where it is stored. When the supraoptic and paraventricular nuclei in the hypothalamus are stimulated by increased serum osmolality or other factors, nerve impulses travel down the hypothalamohypophysial tract to the posterior pituitary gland, causing the stored ADH to be released into the circulation. ADH exerts its effects through two types of vasopressin (V) receptors-V1 and V2. V1 receptors, which are located in vascular smooth muscle, cause vasoconstriction . Although ADH can increase blood pressure through V1 receptors, this response occurs only when ADH levels are very high. The V2 receptors, which are located on the tubular cells of the cortical collecting duct, control water reabsorption by the kidney. These renal mechanisms for water reabsorption are responsible for maintaining the osmolality of body fluids.

The mechanism whereby ADH acts on the tubular cells to increase water reabsorption has recently been elucidated. Without ADH, the luminal membranes of the tubular epithelial cells of the collecting ducts are almost impermeable to water. In the presence of ADH, pores or water channels, called aquaporins, are inserted into the membrane of these tubular cells, making them permeable to water. T he specific water channel that is controlled by ADH is aquaporin-2.21

The abnormal synthesis and release of ADH occurs in a number of stress situations. Severe pain, nausea, trauma, surgery, certain anesthetic agents, and some narcotics (e.g., morphine and meperidine) increase ADH levels. Among the drugs that affect ADH are nicotine, which stimulates its release, and alcohol, which inhibits it. Two important conditions alter ADH levels: NSIADH (more commonly diagnosed as Diabetes Insipidus) and inappropriate secretion of ADH.

In healthy subjects, arginine vasopressin (AVP) is synthesized in the supraoptic and paraventricular nuclei and acts through the three types of AVP receptors: the V1a receptor (vasopressive effects of AVP), the V1b receptor found in the adenohypophysis (ACTH secretion), and the V2 receptor (V2R) localized in the distal renal collecting duct [8]. Binding to the V2R stimulates cAMP production through the Gαs and adenyl cyclise [9]. Subsequent phosphorylation of AQP2 by the cAMP-dependent protein kinase (PKA) is suggested to promote the insertion of AQP2 into the apical membrane of the principal cells of renal collecting duct, resulting in enhanced reabsoption of free water [8]. This negative regulation of the V2R after stimulation by AVP prevents prolonged and excessive tubular reabsorption of water [10]. In NSIAD, the constitutively active mutant V2R appears to lose this important property, at least partly [11].The ability of the mutant V2R to induce cAMP, as measured by cAMP-inducible luciferase reporter in COS-7 cells, was 4-7.5-fold increased compared with the wildtype V2R [11]. This gain of function due to constitutive activation of V2R in NSIAD patients explains inappropriate antidiuresis [9]. G protein-coupled receptors constitute the largest gene family of receptors involved in signal transduction and are responsible for regulating many physiological processes [12], and mutations that render the receptors unresponsive to ligand [12], has been linked to gain-of-function mutations, resulting in constitutive activation [13]. The mutations in NSIADH involve the arginine residue at the position 137 [14-15]. This residue is highly conserved and is a part of the DRY/H motif, located at the junction of the third transmembrane domain and the second intracellular loop [16]. The V2R-R137C and V2R-R137L mutants traffic more efficiently to the plasma membrane compared with the V2R-R137H mutant [16]. The latter mutation is a cause of nephrogenic diabetes insipidus (NDI) due to impaired trafficking [15-16].

Normally, G-protein-mediated signalling is a subject of extensive negative regulation. A decrease in the negative regulation would prolong the cellular response to an activated receptor. Upon binding of AVP, multiple serine residues in the V2R terminus are phosphorylated by Gprotein- coupled receptor kinases [17]. The phosphorylated receptors recruit arrestins. Arrestin binding to activated receptors promotes desentization by interrupting receptor- G-protein coupling, with simultaneously recruiting of the clathrin-dependent endocytotic machinery and lysosomal degradation [17]. It was hypothesized that activating V2R mutants might have impaired β arrestin binding. Thus, impaired arrestin binding cannot explain the constitutive activation of the V2R. Recent study has further characterized V2R-R137H (causing NDI) compared with V2R-R137C and V2RR137L (causing NSIAD) [18]. All three mutants showed both impaired maturation (reduced Golgi processing) and elevated constitutional endocytosis resulting in a reduced steady-state surface expression [18]. The elevated endocytosis may reduce the severity of NSIAD while the constitutional activation of V2R-R137C and V2R-R137L remains unexplained [19].

Was the fluid restriction and administration of an osmotic agent effective in treating NSIAD?

In symptomatic NSIAD patients with hyponatremia, rapid management with fluid restriction and, if necessary, administration of 30-50% oral urea solution, is necessary to avoid persistent or increased hyponatremia, which carries the risk of brain damage [19-20]. Fluid restriction alone, the simplest treatment, is not feasible during infancy as caloric deficiency would be the consequence [20]. AVPR2 inverse agonist SR121463 have been recently tested and failed to decrease the constitutive activity of V2R-c- R137L mutants and increased R137C-V2R cell-surface targeting [21], consistent with its inactivity in NSIAD patients carrying the R137C-V2R mutation [19-21]. The observed in vitro effect of ADH, however, is rather small, and when high doses are needed, the extrarenal actions on V1a and V1b receptors should be considered [21]. Extensive experience with the use of oral urea [22] or a single oral dose of furosemide with salt supplementation [23] has been reported in patients with SIADH and can be applied in NSIAD patients. Successful use of oral urea has been reported in patients with NSIAD [20, 21, and 23]. After early childhood, the symptoms of NSIAD usually decrease, as children can often self-regulate fluid intake, and all other treatments might be discontinued [24]. Furosemide has not yet been tested in patients with NSIAD, but is of potential benefit, because it decreases the medullar hypertonicity, mitigating the stimulus of the hypertonic environment on the aquaporin 2 expressions and its apical localization in the principal cells of renal collecting duct [25]. More frequent administration of furosemide would be more effective but will also induce electrolyte disturbances such as salt depletion, hypokalaemia and hypercalciuria [26].

Initially, the patient was diagnosed with SIADH before identification of a mutation in the patient. What, then, is the process of incorrectly identifying patients with NSIADH?

When NSIAD is suspected, the plasma sodium level, plasma and urine osmolalities, and plasma AVP level should all be measured at the same time during the hyponatremic episode [27]. The association of hyponatremia with relatively high urine osmolality and a low or undetectable plasma AVP level is an indication for sequencing the AVPR2 [27-28]. In siblings, a waterload test can be performed in an asymptomatic boy but cautiously [27]. In girls, a 20mL/kg water-load test can help to determine their ability to dilute their urine, as this is variable in heterozygous females due to random X inactivation and will help in providing them with recommendations for water intake [28]. Assessment of the concentration of the plasma von Willebrand factor (vWF) antigen, which is known to be increased by AVP stimulation of the so-called "extrarenal V2R," does not seem to be helpful in diagnosing NSIAD patients [29].

Jason Serra Student Number: 364776

Word Count: 1829