Arginine Vasopressin Secretion Research Articles

Turning complexity into clarity: polyuria and hypernatremia

Turning complexity into clarity: polyuria and hypernatremia

Hypervolemic Hyponatremia in Heart Failure.

Heart failure (HF) represents the most common cause of hypervolemic hyponatremia in current clinical practice. The presence of hyponatremia has been independently associated with worse outcomes in this patient population. The pathogenesis of hyponatremia in HF involves complex neurohormonal and cardio-renal interactions, including an increase in non osmotic secretion of arginine vasopressin (AVP) and insufficient tubular flow in the diluting segments of the nephron. The treatment of hyponatremia in HF involves decongestant therapy with diuretics, neurohormonal blockade and in certain occasions the use of AVP antagonists. The aim of this chapter is to summarize the pathophysiology, current evidence, and management recommendations for hyponatremia in patients with HF, with a specific focus on AVP homeostasis.

Differences between Arginine-Vasotocin and Arginine-Vasopressin Effects on the Rat Kidney in Evolution of Osmoregulation in Vertebrates

Arginine-vasotocin (AVT) is a hormone common to most vertebrates except mammals where it is replaced by vasopressin. A study of the effect of both nonapeptides of the vasopressin family [AVT and arginine-vasopressin (AVP)] showed that in the rat kidney they are involved in the regulation of renal sodium and solute-free water reabsorption. These effects are mediated by different subtypes of V-receptors activated by different blood serum concentrations of the hormone. An immunoenzyme assay (ELISA) was proposed to determine AVT concentrations under almost complete inhibition of AVP secretion. When both hormones were administered at equal doses, AVT broke down slower and acted longer than AVP. A high metabolic rate of the nonapeptide in the blood is supposed to be an evolutionary advantage as a tool to upgrade the water-salt balance regulation. The importance of comparing the effects of hormones lost during the evolution of vertebrates as a method to study the evolution of functions is discussed.

105: Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia in mice

The concept that poor fetal tolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion throughout pregnancy phenocopies human PE in mice mirroring the tonically elevated AVP secretion throughout human PE pregnancy. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCreg) promote tolerance via regulatory T cell induction, cell-to-cell interactions, and anti-inflammatory cytokine production. The objective of this study is to determine if DCreg treatment will prevent PE in an AVP-induced mouse model of PE. C57BL/6 dams were infused with AVP (24 ng/hour) or saline throughout gestation via osmotic minipump. To generate DCreg, bone marrow derived cells from C57BL/6 mice were cultured with human TGFβ1 and murine GM- CSF and IL-10. At the time of pump implantation (gestational day, GD -3) or early post-placentation on GD 7, AVP dams received a single intravenous injection of DCreg. Blood pressure was taken throughout pregnancy and total urine protein was measured on GD 18. Maternal tissues were collected on GD 18. Cytokine concentrations were determined via ELISA and normalized to total protein. Treatment of AVP-infused dams with DCreg before mating (GD -3) or on GD 7 prevented PE development. DCreg prevented hypertension (AVP: 120 ±1.8, n=27 vs GD -3: 108 ±3.3, n=7 vs GD 7: 110 ±4.4, n=5 p<0.05) and elevations in proteinuria (AVP: 37.4 ±2.3, n=24 vs GD -3: 25.6 ±2.9, n=7 vs GD 7: 24.1 ±3.1, n=5 p<0.05) (Figure 1). Elevations in pro- inflammatory plasma IFNγ were reversed with treatment (AVP: 27.7 ±12.0, n=6 vs GD -3: 0.0±0.0, n=4 vs GD 7: 0.0±0.0, n=6 pg/g, p<0.05) (Figure 2A). DCreg also reversed suppression of anti-inflammatory TGFβ in the plasma (AVP: 1.3 ± 0.91, n=9 vs GD -3: 3.2 ±0.50, n=4 vs GD 7: 2.9 ±0.25, n=6 ug/g, p<0.05) (Figure 2B). These data support the hypothesis that DCreg treatment prevents AVP-induced PE. It further provides evidence for the potential use of personalized, cellular therapy in the prevention of cardiovascular, renal, and immune alterations induced by preeclampsia.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Relationship between non-osmotic arginine vasopressin secretion and hemoglobin A1c levels in adult patients with congenital heart disease.

Arginine vasopressin (AVP), which induces vasoconstriction and conserves solute-free water when released during high plasma osmolality, is secreted through 2 mechanisms: osmoregulation and baroregulation. This study aims to clarify the mechanisms and influencing factors for non-osmotic AVP secretion in adult patients with congenital heart disease (CHD). AVP levels were measured in 74 adults with CHD. Non-osmotic AVP secretion was defined as excessive AVP secretion relative to the AVP level inferred from plasma osmolality. Accordingly, 10 patients (13.5%) demonstrated non-osmotic AVP secretion, with AVP levels higher than those in patients without non-osmotic AVP secretion (6.4 ± 3.1 vs. 1.6 ± 0.9pg/ml; p < 0.0001). Non-osmotic AVP secretion was significantly correlated with diuretic use [odds ratio (OR) 7.227; confidence interval (CI) 1.743-29.962; p = 0.0006], HbA1c level (OR 11.812; CI 1.732-80.548; p = 0.012), and B-type natriuretic peptide (BNP) level (OR 1.007; CI 1.001-1.012; p = 0.022). Multiple logistic regression analysis revealed that there was a significant association between non-osmotic AVP secretion and HbA1c level (OR 9.958; 1.127-87.979; p = 0.0039), and a nearly significant relationship between non-osmotic AVP secretion and BNP (OR 1.006; CI 1.000-1.012; p = 0.056). In conclusion, this study showed that 13.5% of adult patients with CHD demonstrated non-osmotic AVP secretion, which could be correlated with heart failure and insulin resistance. The AVP system might be one of the mechanisms linking heart failure and the onset of type 2 diabetes mellitus in adults with CHD.

Vasopressin, depression, pain &amp; preeclampsia

Preeclampsia (PreE) is a prevalent hypertensive disorder of pregnancy leading to a death every minute worldwide. Predictive and preventative challenges in PreE stems from its unclear early-pregnancy etiology. Arginine vasopressin (AVP) secretion, as measured by copeptin, activates the stress response system and is a novel, early pregnancy predictor of PreE. In addition, elevated AVP is associated with stress, depression and pain. Our Precision Healthcare goal is to understand how AVP-associated changes in depression and pain affect the phenotype of PreE to develop preventative and therapeutic modalities against it. We hypothesize that in humans, antecedent depression and pain affects early pregnancy AVP secretion/copeptin which will be differentially predictive of PreE. To address this hypothesis we aim to 1) determine the association of maternal plasma copeptin and measures of depression and pain throughout human gestation and 2) determine how depression and pain through gestation affects an early pregnancy copeptin based prediction model of preeclampsia.

Copeptin, a surrogate marker for arginine vasopressin secretion, is positively associated with glucagon

To explore the association of plasma copeptin, the C-terminal portion of provasopressin and a stable surrogate marker for arginine vasopressin secretion, with plasma glucagon in obese men and men of normal weight. We measured fasting blood concentrations ofcopeptin and glucagon in 102 healthy obese men (mean ± sd age 49.4 ± 10.2 years) and a control group 27 healthy men of normal weight (mean ± sd age 51.5 ± 8.4 years). Differences between groups were evaluated using t-tests, and multiple linear regression analysis, adjusting for age and weight status (normal weight vs obese), was used to calculate unstandardized regression coefficients (β) with 95% CIs between copeptin and glucagon. Copeptin was (natural) log-transformed. The obese men had higher [median (interquartile range)] plasma copeptinconcentrations [6.6 (4.6-9.5) vs 4.9 (3.5-6.8) pmol/l; P = 0.040] and higher mean ± sd plasma glucagon concentrations (8.5 ± 3.8 vs 5.3 ± 1.4 pmol/l; P < 0.001) than the normal-weight men. Adjusted for age and weight status, copeptin was significantly associated with glucagon (β = 1.35, 95% CI 0.13-2.57; P = 0.031). No significant interaction effect between copeptin and weight status on glucagon was found (P = 0.81). Obese men had higher concentrations of copeptin and glucagon than men of normal weight. Copeptin was positively associated with glucagon. Our data suggest that increased arginine vasopressin-stimulated glucagon secretion might contribute to higher glucagon concentrations; therefore, increased arginine vasopressin secretion, in addition to other factors, could further aggravate the hyperglucagonaemic state found in obese individuals.

High salt loading increases brain derived neurotrophic factor in supraoptic vasopressin neurones.

High salt loading (SL) is associated with inappropriate arginine vasopressin (AVP) release and increased mean arterial pressure. Previous work has shown that chronic high salt intake impairs baroreceptor inhibition of rat AVP neurones through brain-derived neurotrophic factor (BDNF) dependent activation of tyrosine receptor kinase B (TrkB) and down-regulation of K+/Cl- co-transporter KCC2. This mechanism diminishes the GABAA inhibition of AVP neurones in the supraoptic nucleus (SON) by increasing intracellular chloride. However, the source of BDNF leading to this ionic plasticity is unknown. In the present study, we used adeno-associated viral vectors with short hairpin RNA against BDNF to test whether SON is the source of BDNF contributing to increased AVP release and elevated mean arterial pressure in high salt loaded rats. Virally mediated BDNF knockdown (shBDNF) in the SON of salt loaded rats significantly blocked the increases in BDNF mRNA and AVP heterogeneous RNA expression. The observed increase in the activation of TrkB receptor during salt loading is consistent with previous studies. Western blot analysis of SON punches revealed that tyrosine phosphorylation of TrkB (pTrkBY515) was significantly decreased in salt shBDNF rats compared to the salt scrambled (SCR) rats. Injections of shBDNF in the SON also significantly prevented the increase in plasma AVP concentration associated with salt loading. However, the salt loading induced increase in mean arterial pressure was not decreased with BDNF knockdown in the SON. Average daily fluid intake and urine output were significantly elevated in both salt SCR and salt shBDNF rats compared to the euhydrated controls. Daily average urine sodium concentration was significantly higher in shBDNF injected salt rats than the other groups. These findings indicate that BDNF produced in the SON contributes to the increased AVP secretion during high salt loading but not with respect to the subsequent increase in mean arterial pressure.

Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in mice.

Copeptin, a marker of arginine vasopressin (AVP) secretion, is elevated throughout human pregnancies complicated by preeclampsia (PE), and AVP infusion throughout gestation is sufficient to induce the major phenotypes of PE in mice. Thus, we hypothesized a role for AVP in the pathogenesis of PE. AVP infusion into pregnant C57BL/6J mice resulted in hypertension, renal glomerular endotheliosis, intrauterine growth restriction, decreased placental growth factor (PGF), altered placental morphology, placental oxidative stress, and placental gene expression consistent with human PE. Interestingly, these changes occurred despite a lack of placental hypoxia or elevations in placental fms-like tyrosine kinase-1 (FLT1). Coinfusion of AVP receptor antagonists and time-restricted infusion of AVP uncovered a mid-gestational role for the AVPR1A receptor in the observed renal pathologies, versus mid- and late-gestational roles for the AVPR2 receptor in the blood pressure and fetal phenotypes. These findings demonstrate that AVP is sufficient to initiate phenotypes of PE in the absence of placental hypoxia, and indicate that AVP may mechanistically (independently, and possibly synergistically with hypoxia) contribute to the development of clinical signs of PE in specific subtypes of human PE. Additionally, they identify divergent and gestational time-specific signaling mechanisms that mediate the development of PE phenotypes in response to AVP.

Approach and management of dysnatremias in cirrhosis.

Hypervolemic (dilutional) hyponatremia is the most common dysnatremia in cirrhosis, with a prevalence close to 50% in patients with ascites, while hypovolemic hyponatremia occurs in a minority of cases. Hyponatremia carries a poor prognosis, being associated with increased mortality and reduced survival after liver transplantation. Hypernatremia is rarer and is also associated with an adverse prognosis. Increased non-osmotic secretion of arginine vasopressin and altered renal tubular sodium handling due to impaired free water generation are the mechanisms leading to hypervolemic hyponatremia, while diuretic-induced fluid loss is the main cause of hypovolemic hyponatremia. Hypernatremia usually follows hypotonic fluid losses due to osmotic diuresis (glycosuria) or lactulose-induced diarrhea. The main clinical manifestations of dysnatremias are due to their effects on the central nervous system: astroglial cell hyperhydration follows hyponatremia-an abnormality that exacerbates ammonia neurotoxicity-while the opposite abnormality occurs with hypernatremia. Asymptomatic or mildly symptomatic hypervolemic hyponatremia is mainly managed by correcting of precipitating factors and non-osmotic fluid restriction. Severe, life-threatening hyponatremia requires hypertonic saline infusion, avoiding rapid and complete correction of serum sodium concentration to prevent neurological sequelae such as osmotic demyelination. V2 receptor blockade by vaptans may be considered in patients with sustained hyponatremia waitlisted for liver transplantation. Diuretic withdrawal and plasma volume expansion are required in hypovolemic hypernatremia. Prompt recognition, removal of the precipitating factor(s) and non-osmotic fluid administration represent the mainstays of hypernatremia management. Rapid correction of long-standing hypernatremia can lead to cerebral edema and has to be avoided.

AB033. Testosterone and nocturia

Nocturia is a major problem in the elderly and can be caused by a range of urologic and nonurologic conditions. Age-associated physiologic, structural, hormonal, and histologic changes play an important role in the increasing incidence of nocturia in elderly patients. Benign prostate hyperplasia (BPH) has been suggested as the main factor triggering nocturia, and therefore, efforts have focused on alleviating BPH through medical or surgical treatment. Although male lower urinary tract symptoms (LUTS) have traditionally been attributed to BPH, many evidences has shown that LUTS in some male patients might be derived from the bladder or systemic conditions. Recent investigations have reported that factors such as aging, late onset hypogonadism (LOH), and sleep disturbances are associated with nocturia. An increased prevalence of nocturia in elderly men is also caused by many factors other than BPH. Impaired kidney responsiveness to arginine vasopressin (AVP) and disrupted circadian nocturnal AVP secretion has been reported as a possible mechanism of nocturnal polyuria in older patients. Lack of sleep because of nocturia affects normal physiological actions in the human body, especially testosterone secretion. It is mostly secreted in the early morning and decreases to its minimum level after sleep. Therefore, sleep disturbances are believed to affect the pulsatile secretion of testosterone, and when sleep disturbances improve, testosterone secretion is expected to improve as well. Currently, it has not yet been revealed which of the following occurs first: nocturia-induced stress decreases testosterone levels or age induces decreased testosterone levels, which causes nocturia. Although the mechanism of action is still unknown, we suggest that desmopressin could correct disturbances of the circadian regulation of testosterone secretion. Because many factors are involved in testosterone and nocturia, further studies are needed to confirm our findings.

Vasopressin and oxytocin in sensory neurones: expression, exocytotic release and regulation by lactation

The neurohormones arginine-vasopressin (AVP) and oxytocin (OT) synthesised in supraoptic and paraventricular nuclei of neurohypophysis regulate lactation, systemic water homeostasis and nociception. Using transgenic rats expressing AVP and OT tagged with fluorescent proteins we demonstrate that both neurohormones are expressed in sensory neurones both in vitro, in primary cultures, and in situ, in the intact ganglia; this expression was further confirmed with immunocytochemistry. Both neurohormones were expressed in nociceptive neurones immunopositive to transient receptor potential vannilloid 1 (TRPV1) channel antibodies. The AVP and OT-expressing DRG neurones responded to AVP, OT, 50 mM K+ and capsaicin with [Ca2+]i transients; responses to AVP and OT were specifically blocked by the antagonists of V1 AVP and OT receptors. Probing the extracellular incubation saline with ELISA revealed AVP and OT secretion from isolated DRGs; this secretion was inhibited by tetanus toxin (TeNT) indicating the role for vesicular release. Expression of OT, but not AVP in DRG neurones significantly increased during lactation. Together, the results indicate novel physiological roles (possibly related to nociception and mood regulation) of AVP and OT in the sensory neurones.

Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus

Sepsis is one of the leading causes of mortality in intensive care units besides causing profound alterations in the brain. One of the structures notably affected during sepsis is the hypothalamus, resulting in important physiopathological consequences. Recently, we provided evidence that the presence of neuroinflammation, oxidative stress, and apoptosis in the hypothalamus of septic rats, is accompanied by impairment of arginine vasopressin (AVP) secretion. We had also demonstrated that sepsis survivor animals present attenuated AVP secretion after osmotic challenge, suggesting a persistent inflammation in the hypothalamus. However, the long-term course of inflammation in the hypothalamus remains unclear. Thus, we induced sepsis by cecal ligation and puncture (CLP) in Wistar rats and, five days after sepsis induction, the hypothalamus of each animal was collected for analysis. Nonmanipulated animals (naive) were used as controls. We found that CLP-induced morphological alterations in microglial cells are accompanied by an increase in Iba-1 immunoreactivity. Moreover, we observed enhanced expression of NF-κB and CREB transcription factors, which are well known to modulate the immune response. Additionally, we found that phosphorylation of GSK3α/β (a kinase upstream to the CREB signaling pathway) was increased, as well as COX-2, iNOS, and IL-6 that are canonic inflammatory proteins. Thus, our results indicated the presence of sustained activation of resident glial cells that may result in neuroinflammation and cholinergic neurotransmission disruptions in the hypothalamus.

Modulation of synaptic inputs in magnocellular neurones in a rat model of cancer cachexia.

In cancer cachexia, abnormal metabolism and neuroendocrine dysfunction cause anorexia, tissue damage and atrophy, which can in turn alter body fluid balance. Arginine vasopressin, which regulates fluid homeostasis, is secreted by magnocellular neurosecretory cells (MNCs) of the hypothalamic supraoptic nucleus. Arginine vasopressin secretion by MNCs is regulated by both excitatory and inhibitory synaptic activity, alterations in plasma osmolarity and various peptides, including angiotensin II. In the present study, we used whole-cell patch-clamp recordings of brain slices to determine whether hyperosmotic stimulation and/or angiotensin II potentiate excitatory synaptic input in a rat model of cancer cachexia, similar to their effects in normal (control) rats. Hyperosmotic (15 and 60 mmolL-1 mannitol) stimulation and angiotensin II (0.1μmolL-1 ) increased the frequency, but not the amplitude, of miniature excitatory postsynaptic currents in normal rats; in model rats, both effects were significantly attenuated. These results suggest that cancer cachexia alters supraoptic MNC sensitivity to osmotic and angiotensin II stimulation.

Alterations in hypothalamic synaptophysin and death markers may be associated with vasopressin impairment in sepsis survivor rats.

The impairment in arginine vasopressin (AVP) secretion during sepsis is described in clinical and experimental studies and has been associated with oxidative stress, apoptosis, and diminished activation of hypothalamic neurons. Few studies have, however, assessed these abnormalities in sepsis survivors. Here we performed two sets of experiments on Wistar rats that had been subjected to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. In the first set, tissues and blood were collected from survivor rats 10 days after CLP to quantify hypothalamic Bcl-2, cleaved caspase- 3 and synaptophysin content, and bacterial load. In the second set, survivor rats were submitted to an acute osmotic stimulus (hypertonic saline), and after 30 minutes the water intake and AVP secretion were analyzed. The sepsis-surviving rats did not show bacterial load in tissues, but their hypothalamic synaptophysin and Bcl-2 levels were decreased, and the cleaved caspase- 3 level was increased when compared with the control group. However, AVP secretion was significantly attenuated in the CLP survivor animals submitted to an acute osmotic stimulus. These results suggest that the persistent AVP impairment in sepsis survivor animals may be due to a hypothalamic dysfunction associated with a synaptic deficit and decreased anti-apoptotic protein expression. This article is protected by copyright. All rights reserved.

Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure.

AimsThe arginine vasopressin (AVP) pathway has been extensively studied in heart failure (HF) with reduced ejection fraction (HFrEF), but less is known about AVP in HF with preserved EF (HFpEF). Furthermore, the association between AVP and atrial natriuretic peptide (ANP, a well‐known inhibitor of AVP secretion) in HF is unknown.Methods and resultsWe studied subjects with HFpEF (n = 28) and HFrEF (n = 25) and without HF (n = 71). Left ventricular (LV) mass and left atrial (LA) volumes were measured with cardiac magnetic resonance imaging. Arginine vasopressin and ANP were measured with enzyme‐linked immunosorbent assay. Arginine vasopressin levels were significantly greater in HFpEF [0.96 pg/mL; 95% confidence interval (CI) = 0.83–1.1 pg/mL] compared with subjects without HF (0.69 pg/mL; 95% CI = 0.6–0.77 pg/mL; P = 0.0002). Heart failure with preserved ejection fraction (but not HFrEF) was a significant predictor of higher AVP after adjustment for potential confounders. Arginine vasopressin levels were independently associated with a greater LA volume and also paradoxically, with lower ANP levels. Key independent correlates of higher AVP were the presence of HFpEF (standardized β = 0.32; 95% CI = 0.09–0.56; P = 0.0073) and the ANP/LA volume ratio (standardized β = −0.23; 95% CI = −0.42 to −0.04; P = 0.0196). Arginine vasopressin levels were independently associated with LV mass (β = 0.26; 95% CI = 0.09–0.43; P = 0.003) and with an increased risk of death or HF admissions during follow‐up (hazard ratio = 1.61; 95% CI = 1.13–2.29; P = 0.008).ConclusionsArginine vasopressin is increased in HFpEF and is associated with LV hypertrophy and poor outcomes. Higher AVP is associated with the combination of LA enlargement and paradoxically low ANP levels. These findings may indicate that a relative deficiency of ANP (an inhibitor of AVP secretion) in the setting of chronically increased LA pressure may contribute to AVP excess.

Foreword

Decompensated or acute heart failure (AHF) is characterized by increased ventricular and atrial pressures which may lead to and be caused by circulatory congestion. Unless due to a primary decrease in cardiac function, congestion arises from volume expansion or vasoconstriction. In turn, volume expansion and vasoconstriction are due to neurohormonal imbalance since both result from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis and excess secretion of arginine vasopressin. Outcomes in AHF remain dismal. Loop diuretics are the mainstay of therapy for AHF and may themselves aggravate neurohormonal imbalance. No adjunctive pharmacotherapy has yielded improvement in outcomes in AHF despite many attempts with various vasodilators and inotropes. We, therefore, propose that insufficient attention has been paid to neurohormonal imbalance in AHF. As in chronic HF, rectifying the effects of neurohormonal imbalance may lead to better outcomes. The use of alternative decongestive strategies or adjunctive pharmacotherapy directed at neurohormonal activation could yield benefit.

Arginine Vasopressin Infusion In C57BL/6J Mice Induces Changes In The Placenta Transcriptome That Parallel Changes Observed In Placenta From Human Preeclampsia

Preeclampsia (PE), a cardiovascular disorder of late pregnancy characterized by new onset hypertension and proteinuria, remains a devastating disease affecting approximately 10% of all pregnancies in the United States. Multiple independent studies demonstrate a correlation between PE and elevated maternal plasma copeptin, the C‐terminal fragment of arginine vasopressin (AVP), which supports the concept that AVP secretion is elevated during PE. Previously we demonstrated the sufficiency of chronic low‐dose AVP infusion to initiate major phenotypes of PE in pregnant C57BL/6J mice, including hypertension, renal glomerular endotheliosis, intrauterine growth restriction, and altered placental morphology. Thus, we generally hypothesize that elevated AVP secretion is mechanistically involved in the pathogenesis of PE. Here, we tested the hypothesis that chronic infusion of AVP during gestation in mice would cause changes in the placental transcriptome which parallel changes documented in human PE. Placentas were collected on gestational day 12.5 from mice that received chronic saline or AVP (24 ng/hr) infusion through pregnancy and RNA‐sequencing was performed. Differential expression analyses revealed 87 transcripts, corresponding to 82 unique genes as well as 3 non‐coding RNAs, that were differentially expressed between AVP‐ and saline‐treated placentas (FDR &lt; 0.1). Among the differentially expressed genes identified, six genes (Trpm2, Itih4, Ncmap, Sema3f, Scnn1g, Nfat5) had been previously associated with human PE. Ingenuity Pathway Analysis (IPA) identified that the disease and functional annotations significantly altered in AVP‐treated placentas included hypertension, preeclampsia, as well as cell death. As expected, IPA also identified likely canonical upstream mediators including AVP, desmopressin, and calcium signaling. Notably, Gene Set Enrichment Analysis (GSEA) and IPA did not uncover any enrichment for hypoxia‐associated signaling, suggesting that despite the PE‐like morphological and genetic signatures induced by AVP, AVP does not induce these phenotypes via placental hypoxia. Parallel in silico re‐analyses of a large published dataset from NCBI‐GEO (GSE75010) describing the transcriptomes of control and PE human placentas with various clinical covariates demonstrated that some subtypes of human PE similarly do not exhibit placental hypoxia. Collectively, these data highlight molecular phenotypes of PE induced within the placenta of mice by AVP, and highlight the potential utility of the AVP infusion approach to model specific subtypes of human PE.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Muscarinic M2 receptor promotes vasopressin synthesis in mice supraoptic nuclei.

Muscarinic acetylcholine receptors have been suggested to be implicated in arginine-vasopressin secretion because intracerebroventricular muscarinic agonist administration induces arginine-vasopressin release into the circulation. Although which subtype is involved in the regulation of arginine-vasopressin secretion is unclear, M2 receptors have been reported to be highly expressed in the hypothalamus. In the present study, M2 receptor-knockout mice were used to elucidate whether M2 receptor regulates arginine-vasopressin synthesis in the paraventricular nuclei and supraoptic nuclei of the hypothalamus. The number of arginine-vasopressin-immunoreactive neurons in M2 receptor-knockout mice was significantly decreased in the supraoptic nuclei, but not in the paraventricular nuclei compared with wild-type mice. Plasma arginine-vasopressin level in M2 receptor-knockout mice was also significantly lower than in the wild-type mice. Urinary volume and frequency as well as water intake in M2 receptor-knockout mice were significantly higher than those in wild-type mice. The V2 vasopressin receptor expression in kidneys of M2 receptor-knockout mice was comparable with that of wild-type mice, and increased urination in M2 receptor-knockout mice was significantly decreased by administration of desmopressin, a specific V2 receptor agonist, suggesting that V2 receptors in the kidneys of M2 receptor-knockout mice are intact. These results suggest that M2 receptors promote arginine-vasopressin synthesis in the supraoptic nuclei and play a role in the regulation and maintenance of body fluid.

Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis.

Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.