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Fulltext Control of Polyamine Biosynthesis by Antizyme Inhibitor 1 Is Important for Transcriptional Regulation of Arginine Vasopressin in the Male Rat Hypothalamus

Greenwood MP, Greenwood M, Paton JF, Murphy D

Endocrinology, 2015 Aug;156(8):2905-17.
PMID: 25961839 DOI: 10.1210/en.2015-1074

The polyamines spermidine and spermine are small cations present in all living cells. In the brain, these cations are particularly abundant in the neurons of the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, which synthesize the neuropeptide hormones arginine vasopressin (AVP) and oxytocin. We recently reported increased mRNA expression of antizyme inhibitor 1 (Azin1), an important regulator of polyamine synthesis, in rat SON and PVN as a consequence of 3 days of dehydration. Here we show that AZIN1 protein is highly expressed in both AVP- and oxytocin-positive magnocellular neurons of the SON and PVN together with antizyme 1 (AZ1), ornithine decarboxylase, and polyamines. Azin1 mRNA expression increased in the SON and PVN as a consequence of dehydration, salt loading, and acute hypertonic stress. In organotypic hypothalamic cultures, addition of the irreversible ornithine decarboxylase inhibitor DL-2-(difluoromethyl)-ornithine hydrochloride significantly increased the abundance of heteronuclear AVP but not heteronuclear oxytocin. To identify the function of Azin1 in vivo, lentiviral vectors that either overexpress or knock down Azin1 were stereotaxically delivered into the SON and/or PVN. Azin1 short hairpin RNA delivery resulted in decreased plasma osmolality and had a significant effect on food intake. The expression of AVP mRNA was also significantly increased in the SON by Azin1 short hairpin RNA. In contrast, Azin1 overexpression in the SON decreased AVP mRNA expression. We have therefore identified AZIN1, and hence by inference, polyamines as novel regulators of the expression of the AVP gene.

Matched MeSH terms: Arginine Vasopressin/genetics*; Arginine Vasopressin/metabolism
Fulltext The effects of aging on biosynthetic processes in the rat hypothalamic osmoregulatory neuroendocrine system

Greenwood MP, Greenwood M, Romanova EV, Mecawi AS, Paterson A, Sarenac O, et al.

Neurobiol Aging, 2018 05;65:178-191.
PMID: 29494864 DOI: 10.1016/j.neurobiolaging.2018.01.008

Elderly people exhibit a diminished capacity to cope with osmotic challenges such as dehydration. We have undertaken a detailed molecular analysis of arginine vasopressin (AVP) biosynthetic processes in the supraoptic nucleus (SON) of the hypothalamus and secretory activity in the posterior pituitary of adult (3 months) and aged (18 months) rats, to provide a comprehensive analysis of age-associated changes to the AVP system. By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, we identified differences in pituitary peptides, including AVP, in adult and aged rats under both basal and dehydrated states. In the SON, increased Avp gene transcription, coincided with reduced Avp promoter methylation in aged rats. Based on transcriptome data, we have previously characterized a number of novel dehydration-induced regulatory factors involved in the response of the SON to osmotic cues. We found that some of these increase in expression with age, while dehydration-induced expression of these genes in the SON was attenuated in aged rats. In summary, we show that aging alters the rat AVP system at the genome, transcriptome, and peptidome levels. These alterations however did not affect circulating levels of AVP in basal or dehydrated states.

Matched MeSH terms: Arginine Vasopressin/biosynthesis*; Arginine Vasopressin/genetics*; Arginine Vasopressin/secretion
Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders

Karanth L, Barua A, Kanagasabai S, Nair S

Cochrane Database Syst Rev, 2015 Sep 09.
PMID: 26350784 DOI: 10.1002/14651858.CD009824.pub3

BACKGROUND: Congenital bleeding disorders can cause obstetric haemorrhage during pregnancy, labour and following delivery. Desmopressin acetate is found to be an effective drug which can reduce the risk of haemorrhage and can also stop bleeding in certain congenital bleeding disorders. Its use in pregnancy has been controversial. Hence beneficial and adverse effects of desmopressin acetate in these groups of pregnant women should be evaluated.This is an update of a Cochrane review first published in 2013.
OBJECTIVES: To determine the efficacy of desmopressin acetate in preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant and abstract books of conferences proceedings. We also searched for any randomised controlled trials in a registry of ongoing trials and the reference lists of relevant articles and reviews.Date of most recent search: 18 June 2015.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials investigating the efficacy of desmopressin acetate versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible.
DATA COLLECTION AND ANALYSIS: No trials matching the selection criteria were eligible for inclusion.
MAIN RESULTS: No trials matching the selection criteria were eligible for inclusion.
AUTHORS' CONCLUSIONS: The review did not identify any randomised controlled trials investigating the relative effectiveness of desmopressin acetate for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with desmopressin acetate.Given the ethical considerations, future randomised controlled trials are unlikely. However, other high quality controlled studies (such as risk allocation designs, sequential design, parallel cohort design) to investigate the risks and benefits of using desmopressin acetate in this population are needed.

Matched MeSH terms: Deamino Arginine Vasopressin/therapeutic use*
Fulltext Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders

Karanth L, Barua A, Kanagasabai S, Nair NS

Cochrane Database Syst Rev, 2019 02 13;2:CD009824.
PMID: 30758840 DOI: 10.1002/14651858.CD009824.pub4

BACKGROUND: Congenital bleeding disorders can cause obstetric haemorrhage during pregnancy, labour and following delivery. Desmopressin acetate (DDAVP) is found to be an effective drug which can reduce the risk of haemorrhage and can also stop bleeding in certain congenital bleeding disorders. Its use in pregnancy has been controversial. Hence beneficial and adverse effects of DDAVP in these groups of pregnant women should be evaluated.This is an update of a Cochrane Review first published in 2013 and updated in 2015.
OBJECTIVES: To evaluate the efficacy and safety of DDAVP in preventing and treating acute bleeding in pregnant women with bleeding disorders.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant and abstract books of conferences proceedings. We also searched several clinical trial registries and grey literature (27 August 2017).Date of most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register: 01 October 2018.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials investigating the efficacy of DDAVP versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible.
DATA COLLECTION AND ANALYSIS: No trials matching the selection criteria were eligible for inclusion.
MAIN RESULTS: No trials matching the selection criteria were eligible for inclusion.
AUTHORS' CONCLUSIONS: No randomised controlled trials were identified investigating the relative effectiveness of DDAVP for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high-quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with DDAVP.Given the ethical considerations, future randomised controlled trials are unlikely. However, other high-quality controlled studies (such as risk allocation designs, sequential design, parallel cohort design) to investigate the risks and benefits of using DDAVP in this population are needed.Given that there are unlikely to be any trials published in this area, this review will no longer be regularly updated.

Matched MeSH terms: Deamino Arginine Vasopressin/therapeutic use*
Fulltext RNA binding protein Caprin-2 is a pivotal regulator of the central osmotic defense response

Konopacka A, Greenwood M, Loh SY, Paton J, Murphy D

Elife, 2015 Nov 12;4.
PMID: 26559902 DOI: 10.7554/eLife.09656

In response to an osmotic challenge, the synthesis of the antidiuretic hormone arginine vasopressin (AVP) increases in the hypothalamus, and this is accompanied by extension of the 3' poly(A) tail of the AVP mRNA, and the up-regulation of the expression of RNA binding protein Caprin-2. Here we show that Caprin-2 binds to AVP mRNAs, and that lentiviral mediated shRNA knockdown of Caprin-2 in the osmotically stimulated hypothalamus shortens the AVP mRNA poly(A) tail at the same time as reducing transcript abundance. In a recapitulated in vitro system, we confirm that Caprin-2 over-expression enhances AVP mRNA abundance and poly(A) tail length. Importantly, we show that Caprin-2 knockdown in the hypothalamus decreases urine output and fluid intake, and increases urine osmolality, urine sodium concentration, and plasma AVP levels. Thus Caprin-2 controls physiological mechanisms that are essential for the body's response to osmotic stress.

Matched MeSH terms: Arginine Vasopressin/genetics
Fulltext The treatment of primary nocturnal enuresis in Malaysia

Kanaheswari Y

Med J Malaysia, 2006 Dec;61(5):608-15.
PMID: 17623963 MyJurnal

To determine treatment outcomes in Malaysian children with primary nocturnal enuresis using both non-pharmacological methods and oral desmopressin. Data was collected prospectively from children aged 6-18 years who were referred to the Hospital UKM Enuresis Clinic. Treatment was given to those with a baseline wetting frequency of at least six wet nights/14 nights. Three modalities were offered: fluid management, reward system and oral desmopressin. Response was recorded as partial (> or = 50% reduction in WN from baseline) or full (completely dry). Seventy-one healthy children completed 12 weeks of therapy. Twenty-three children (32.4%) responded to non-pharmacological methods alone (4 full and 19 partial). Another 37 children (51.2%) responded to oral desmopressin (32 to 0.2mg, 4 to 0.4mg and 1 to 0.6mg). Thirty-two percent became dry whilst on therapy. The mean wetting frequency during treatment was significantly reduced (p < 0.01) compared to the baseline mean for both the non-pharmacological group and the desmopressin group. Discontinuation of desmopressin after 12 weeks increased the wetting frequency but this was still significantly lower than at baseline (p < 0.01). No adverse ents were recorded. Treatment of primary nocturnal enuresis in Malaysian children is both effective and well tolerated using fluid management strategies, reward systems and oral desmopressin.

Study site: Hospital UKM Enuresis Clinic

Matched MeSH terms: Deamino Arginine Vasopressin/therapeutic use*
Fulltext Transcription factor CREB3L1 mediates cAMP and glucocorticoid regulation of arginine vasopressin gene transcription in the rat hypothalamus

Greenwood M, Greenwood MP, Mecawi AS, Loh SY, Rodrigues JA, Paton JF, et al.

Mol Brain, 2015 Oct 26;8(1):68.
PMID: 26503226 DOI: 10.1186/s13041-015-0159-1

BACKGROUND: Arginine vasopressin (AVP), a neuropeptide hormone that functions in the regulation of water homeostasis by controlling water re-absorption at kidneys, is synthesised in supraoptic nucleus and paraventricular nucleus of the hypothalamus. An increase in plasma osmolality stimulates secretion of AVP to blood circulation and induces AVP synthesis in these nuclei. Although studies on mechanism of AVP transcriptional regulation in hypothalamus proposed that cAMP and glucocorticoids positively and negatively regulate Avp expression, respectively, the molecular mechanisms have remained elusive. Recently, we identified CREB3L1 (cAMP-responsive element binding protein 3 like 1) as a putative transcription factor of Avp transcription in the rat hypothalamus. However the mechanism of how CREB3L1 is regulated in response of hyperosmotic stress in the neurons of hypothalamus has never been reported. This study aims to investigate effect of previously reported regulators (cAMP and glucocorticoid) of Avp transcription on transcription factor CREB3L1 in order to establish a molecular explanation for cAMP and glucocorticoids effect on AVP expression.
RESULTS: The effect of cAMP and glucocorticoid treatment on Creb3l1 was investigated in both AtT20 cells and hypothalamic organotypic cultures. The expression of Creb3l1 was increased in both mRNA and protein level by treatment with forskolin, which raises intracellular cAMP levels. Activation of cAMP by forskolin also increased Avp promoter activity in AtT20 cells and this effect was blunted by shRNA mediated silencing of Creb3l1. The forskolin induced increase in Creb3l1 expression was diminished by combined treatment with dexamethasone, and, in vivo, intraperitoneal dexamethasone injection blunted the increase in Creb3l1 and Avp expression induced by hyperosmotic stress.
CONCLUSION: Here we shows that cAMP and glucocorticoid positively and negatively regulate Creb3l1 expression in the rat hypothalamus, respectively, and regulation of cAMP on AVP expression is mediated through CREB3L1. This data provides the connection between CREB3L1, a newly identified transcription factor of AVP expression, with the previously proposed mechanism of Avp transcription which extends our understanding in transcription regulation of Avp in the hypothalamus.

Matched MeSH terms: Arginine Vasopressin/genetics*; Arginine Vasopressin/metabolism
Nocturia in patients with benign prostatic hyperplasia: evaluating the significance of ageing, co-morbid illnesses, lifestyle and medical therapy in treatment outcome in real life practice

Singam P, Hong GE, Ho C, Hee TG, Jasman H, Inn FX, et al.

Aging Male, 2015 Jun;18(2):112-7.
PMID: 25690022 DOI: 10.3109/13685538.2015.1011614

The aim of study was to evaluate the influence of ageing, lifestyle, and co morbid illnesses on treatment outcome of nocturia among men with BPH.

Matched MeSH terms: Deamino Arginine Vasopressin/therapeutic use
Fulltext A comparison of physiological and transcriptome responses to water deprivation and salt loading in the rat supraoptic nucleus

Greenwood MP, Mecawi AS, Hoe SZ, Mustafa MR, Johnson KR, Al-Mahmoud GA, et al.

Am J Physiol Regul Integr Comp Physiol, 2015 Apr 01;308(7):R559-68.
PMID: 25632023 DOI: 10.1152/ajpregu.00444.2014

Salt loading (SL) and water deprivation (WD) are experimental challenges that are often used to study the osmotic circuitry of the brain. Central to this circuit is the supraoptic nucleus (SON) of the hypothalamus, which is responsible for the biosynthesis of the hormones, arginine vasopressin (AVP) and oxytocin (OXT), and their transport to terminals that reside in the posterior lobe of the pituitary. On osmotic challenge evoked by a change in blood volume or osmolality, the SON undergoes a function-related plasticity that creates an environment that allows for an appropriate hormone response. Here, we have described the impact of SL and WD compared with euhydrated (EU) controls in terms of drinking and eating behavior, body weight, and recorded physiological data including circulating hormone data and plasma and urine osmolality. We have also used microarrays to profile the transcriptome of the SON following SL and remined data from the SON that describes the transcriptome response to WD. From a list of 2,783 commonly regulated transcripts, we selected 20 genes for validation by qPCR. All of the 9 genes that have already been described as expressed or regulated in the SON by osmotic stimuli were confirmed in our models. Of the 11 novel genes, 5 were successfully validated while 6 were false discoveries.

Matched MeSH terms: Arginine Vasopressin/blood
Fulltext Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus

Greenwood M, Bordieri L, Greenwood MP, Rosso Melo M, Colombari DS, Colombari E, et al.

J Neurosci, 2014 Mar 12;34(11):3810-20.
PMID: 24623760 DOI: 10.1523/JNEUROSCI.4343-13.2014

Arginine vasopressin (AVP) is a neurohypophysial hormone regulating hydromineral homeostasis. Here we show that the mRNA encoding cAMP responsive element-binding protein-3 like-1 (CREB3L1), a transcription factor of the CREB/activating transcription factor (ATF) family, increases in expression in parallel with AVP expression in supraoptic nuclei (SONs) and paraventicular nuclei (PVNs) of dehydrated (DH) and salt-loaded (SL) rats, compared with euhydrated (EH) controls. In EH animals, CREB3L1 protein is expressed in glial cells, but only at a low level in SON and PVN neurons, whereas robust upregulation in AVP neurons accompanied DH and SL rats. Concomitantly, CREB3L1 is activated by cleavage, with the N-terminal domain translocating from the Golgi, via the cytosol, to the nucleus. We also show that CREB3L1 mRNA levels correlate with AVP transcription level in SONs and PVNs following sodium depletion, and as a consequence of diurnal rhythm in the suprachiasmatic nucleus. We tested the hypothesis that CREB3L1 activates AVP gene transcription. Both full-length and constitutively active forms of CREB3L1 (CREB3L1CA) induce the expression of rat AVP promoter-luciferase reporter constructs, whereas a dominant-negative mutant reduces expression. Rat AVP promoter deletion constructs revealed that CRE-like and G-box sequences in the region between -170 and -120 bp are important for CREB3L1 actions. Direct binding of CREB3L1 to the AVP promoter was shown by chromatin immunoprecipitation both in vitro and in the SON itself. Injection of a lentiviral vector expressing CREB3L1CA into rat SONs and PVNs resulted in increased AVP biosynthesis. We thus identify CREB3L1 as a regulator of AVP transcription in the rat hypothalamus.

Matched MeSH terms: Arginine Vasopressin/genetics*
Fulltext A case of persistent hyponatraemia due to reset osmostat

Rohana AG, Norasyikin AW, Suehazlyn Z, Ming W, Norlela S, Norazmi MK

Med J Malaysia, 2006 Dec;61(5):638-40.
PMID: 17623970 MyJurnal

We report a case of a 65 year old Malay lady with long-standing diabetes mellitus, who presented to our institution with a one month history of worsening neck pain and progressive upper and lower limb weakness. She was stable despite severe hyponatraemia which was initially treated as syndrome of inappropriate anti-diuretic hormone (SIADH). This was consistent with her underlying illness which was concluded as cervical tuberculosis (TB) with spinal cord compression. She underwent decompression and bone grafting. Despite continuous treatment her serum sodium levels remained low. There were no other problems with her adrenals or thyroid. A water loading and hypertonic saline perfusion test was performed and supported the diagnosis of reset osmostat. Her serum sodium remained below the normal range and she was discharged well.

Matched MeSH terms: Deamino Arginine Vasopressin
Oestradiol effects on neuroendocrine responses induced by water deprivation in rats

Vilhena-Franco T, Mecawi AS, Elias LL, Antunes-Rodrigues J

J Endocrinol, 2016 Nov;231(2):167-180.
PMID: 27613338

Water deprivation (WD) induces changes in plasma volume and osmolality, which in turn activate several responses, including thirst, the activation of the renin-angiotensin system (RAS) and vasopressin (AVP) and oxytocin (OT) secretion. These systems seem to be influenced by oestradiol, as evidenced by the expression of its receptor in brain areas that control fluid balance. Thus, we investigated the effects of oestradiol treatment on behavioural and neuroendocrine changes of ovariectomized rats in response to WD. We observed that in response to WD, oestradiol treatment attenuated water intake, plasma osmolality and haematocrit but did not change urinary volume or osmolality. Moreover, oestradiol potentiated WD-induced AVP secretion, but did not alter the plasma OT or angiotensin II (Ang II) concentrations. Immunohistochemical data showed that oestradiol potentiated vasopressinergic neuronal activation in the lateral magnocellular PVN (PaLM) and supraoptic (SON) nuclei but did not induce further changes in Fos expression in the median preoptic nucleus (MnPO) or subfornical organ (SFO) or in oxytocinergic neuronal activation in the SON and PVN of WD rats. Regarding mRNA expression, oestradiol increased OT mRNA expression in the SON and PVN under basal conditions and after WD, but did not induce additional changes in the mRNA expression for AVP in the SON or PVN. It also did not affect the mRNA expression of RAS components in the PVN. In conclusion, our results show that oestradiol acts mainly on the vasopressinergic system in response to WD, potentiating vasopressinergic neuronal activation and AVP secretion without altering AVP mRNA expression.

Matched MeSH terms: Arginine Vasopressin/analysis; Arginine Vasopressin/secretion; Arginine Vasopressin/agonists
Fulltext Osmoregulation requires brain expression of the renal Na-K-2Cl cotransporter NKCC2

Konopacka A, Qiu J, Yao ST, Greenwood MP, Greenwood M, Lancaster T, et al.

J Neurosci, 2015 Apr 01;35(13):5144-55.
PMID: 25834041 DOI: 10.1523/JNEUROSCI.4121-14.2015

The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABA-mediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats.

Matched MeSH terms: Arginine Vasopressin/blood; Arginine Vasopressin/drug effects

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