Vasopressin Levels Research Articles

Sex-specific differences in the circadian pattern of action potential firing by rat suprachiasmatic nucleus vasopressin neurons.

The suprachiasmatic nucleus (SCN) of the hypothalamus serves as the master circadian clock in mammals. Most SCN neurons express the inhibitory neurotransmitter GABA (gamma amino butyric acid) along with a peptide cotransmitter. Notably, the neuropeptides vasopressin (VP) and vasoactive intestinal peptide (VIP) define two prominent clusters within the SCN: those located in the ventral core (VIP) and those forming the dorsomedial "shell" of the nucleus (VP). Axons emerging from VP neurons in the shell are thought to mediate much of the SCN's output to other brain regions as well as VP release into the cerebrospinal fluid (CSF). Previous work has shown that VP release by SCN neurons is activity dependent and SCN VP neurons fire action potentials at a higher rate during the light phase. Accordingly, CSF VP levels are higher during daytime. Interestingly, the amplitude of the CSF VP rhythm is greater in males than females, suggesting the existence of sex differences in the electrical activity of SCN VP neurons. Here we investigated this hypothesis by performing cell-attached recordings from 1070 SCN VP neurons across the entire circadian cycle in both sexes of transgenic rats that express green fluorescent protein (GFP) driven by the VP gene promoter. Using an immunocytochemical approach we confirmed that >60% of SCN VP neurons display visible GFP. Recordings in acute coronal slices revealed that VP neurons display a striking circadian pattern of action potential firing, but the characteristics of this activity cycle differ in males and females. Specifically, neurons in males reached a significantly higher peak firing frequency during subjective daytime compared to females and the acrophase occurred ~1 h earlier in females. Peak firing rates in females were not significantly different at various phases of the estrous cycle.

Oxytocin and vasopressin levels in maltreated children: A systematic review

Objective: The present study aimed to focus on the neurobiological basis of childhood maltreatment. Method: A systematic review approach was followed by focusing on the possible links among oxytocin, vasopressin, and child maltreatment. The review included research based on data examining the role that being exposed to any kind of maltreatment during childhood plays. The review was not limited to a specific period. However, reviews, systematic reviews, dissertations, congress papers, and studies in languages other than Turkish and English were excluded. The search was concentrated on the Web of Science, PubMed, Science Direct, Scopus, EBSCO Host, and Google Scholar databases including the keyword combinations. Results: The review between December 2021 and April 2022 revealed 49 research studies that reported data from a total of 13979 participants (3981 children and adolescents, 9998 adults). Studies reviewed contained demographically diverse samples from a wide range of Western cultural contexts. Conclusion: The findings are promising in terms of clinical implications as there are considerable links between OXT and child maltreatment. However, more studies are needed to understand the nature of these links.

Relationship between stress levels and endolymphatic space volume in Meniere's disease

ObjectivesSince the first report by Hallpike and Yamakawa in 1938, many more patients with Meniere's disease (MD) with endolymphatic hydrops (EHs) have been described. Mental/physical stress and a subsequent increase in the release of the anti-diuretic hormone (ADH) supposedly triggers MD. In the present study, to assess the relationship between stress and EHs, we conducted a series of stress-related questionnaires as well as a 3D endolymphatic space (ELS) analysis in patients with unilateral MD. MethodsWe enrolled 76 patients with unilateral MD (uMD) as the active group and 75 patients with unilateral benign paroxysmal positional vertigo (uBPPV) as the control group; both underwent examinations between June 2014 and November 2019. All patients underwent 3-T magnetic resonance imaging (MRI) 4 h after intravenous gadolinium injection. We used the total fluid space (TFS), ELS, and ELS rate (ELS/TFS × 100), which is the percentage of the volume of the ELS relative to that of the TFS, for a precise evaluation of the ELS and EHs in MD. Stress was evaluated using the Self-Rating Depression Scale (SDS), the psychological Stress Response Scale (SRS), and the modified Dizziness Handicap Inventory (mDHI). Stress scores and blood ADH levels were compared across patient groups. ResultsIn patients with uMD, ELS rates significantly correlated with SRS scores on both the affected and the healthy side and with mDHI scores on the affected side, while the SDS and ADH showed no significant correlation with the ELS rates. Correlations were much stronger in the group with severe SDS and one with low ADH levels. ConclusionsThe present results indicate that stress may be involved in EHs development in uMD, not only in the ipsilateral but also the contralateral ear. They also suggest that patients with neuropsychiatric tendencies may develop EHs and MD in response to a stressful lifestyle.

MP03-09 PHENOTYPING NOCTURIA IN HYPERTENSIVES ACCORDING TO 24-HOUR URINE COMPOSITION

You have accessJournal of UrologyCME1 Apr 2023MP03-09 PHENOTYPING NOCTURIA IN HYPERTENSIVES ACCORDING TO 24-HOUR URINE COMPOSITION Joseph Boroda, Susan Gong, Frederick Okoye, Syed Rahman, Matthew Moy, Alla Akivis, Jason Lazar, and Jeffrey Weiss Joseph BorodaJoseph Boroda More articles by this author , Susan GongSusan Gong More articles by this author , Frederick OkoyeFrederick Okoye More articles by this author , Syed RahmanSyed Rahman More articles by this author , Matthew MoyMatthew Moy More articles by this author , Alla AkivisAlla Akivis More articles by this author , Jason LazarJason Lazar More articles by this author , and Jeffrey WeissJeffrey Weiss More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003214.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There are numerous comorbidities correlated with nocturia, among the most clinically significant of these being hypertension. Elevation in blood pressure (BP) suppresses serum arginine vasopressin levels, lending evidence to the idea that hypertension is associated pathophysiologically with nocturnal polyuria, which may cause nocturia. Greater nighttime BP and lower nocturnal BP dipping have been associated with more frequent nocturnal voiding. The aim of this study is to assess the impact of non-dipping orthostatic BP in hypertensives on nighttime and daytime urine production. METHODS: Participants with a diagnosis of essential hypertension had in-office supine and standing BP recordings and completed 24-hour urine collection and voiding diaries. Urine was collected in 3 containers; one for the first nighttime void, a second for all subsequent nighttime voids and first morning void, and a third for all daytime voids. Participants whose systolic BP decreased with supine positioning were placed in the orthostatic dip group, and participants whose systolic BP increased or was unchanged upon supine positioning were placed in the no orthostatic dip group. RESULTS: There were 12 (9 female) individuals in the dipping group and 19 (13 female) in the non-dipping group. The non-dipping group tended to produce greater volumes of urine both day and night, and had greater 24-hour urine sodium excretion. The sodium concentration of the first nighttime void was significantly higher in the non-dipping group (median: 102; IQR: 76-105 mEq/L) than the dipping group (median: 51; IQR: 32.5 - 65 mEq/L) (p=.024). This urine sodium concentration for the remainder of the night was significantly higher in the non-dipping group (median: 92; IQR: 62-117 mEq/L) than the dipping group (median: 59.5; IQR: 48-77.25 mEq/L) (p=.012). Subjects in the non-dipping group were 79% more likely to experience 2 or more nighttime voids compared to the dipping group (RR: 1.79; 95% CI: 1 – 3.2; p=.052). CONCLUSIONS: An in-office BP measurement that does not dip with supine positioning is associated with more frequent nighttime voiding as well as higher urine concentrations of sodium in both early and late-night voids. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e24 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joseph Boroda More articles by this author Susan Gong More articles by this author Frederick Okoye More articles by this author Syed Rahman More articles by this author Matthew Moy More articles by this author Alla Akivis More articles by this author Jason Lazar More articles by this author Jeffrey Weiss More articles by this author Expand All Advertisement PDF downloadLoading ...

CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst

BackgroundFatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance.MethodsTo obtain Cpt1aKO mice and their control littermates, Cpt1a(flox/flox) mice were crossed with tamoxifen-inducible AgRPCreERT2 mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting–refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin–angiotensin–aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag–Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex.ResultsChanges in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations.ConclusionsOur results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.

Sugar, salt, immunity and the cause of primary hypertension.

Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension.

Study of Homocysteine, SDMA, ADMA, UMOD, AVP, and KIM-1 in serum of chronic renal disease patients suffering from Type-2 diabetes in Basra Province

Chronic kidney disease (CKD) is a reduction in renal function manifested by a GFR of less than 60 mL/min per 1.73 m2 or kidney damage marker, or maybe both, last about 3 months, regardless of actual cause. Diabetes mellitus (DM) seem to be the causative factors of CKD in all high- middle-income regions, as well as in numerous low country income. Mellitus accounts for 30–50% of all CKD and affects 285 million (6.4%) individuals globally. A case-control study included 30 CKD patients with T2DM and 30 healthy subjects as a control group who visited Al-Basrah Teaching Hospital in Al-Basrah province between October 2021 and February 2022. The Age average for study population was (25-60) years. Serum levels of human AVP, ADMA, KIM-1, HCY, UMOD, and SDMA were measured by a sandwich-ELISA technique. The results revealed a highly significant increase in the levels of homocysteine, SDMA, ADMA, AVP, and KIM-1 in CKD-diabetic patients (P < 0.05) and a highly significant decrease in the level of UMOD (P<0.05) compared to control. According to the results, we conclude: Hyperhomocysteinemia occurs in chronic and end-stage kidney diseases. A potential indicator of renal health, uromodulin allows for the early identification of CKD. This tubular secretion marker may possibly represent intrinsic "kidney function" and residual nephron mass in addition to glomerular filtration. The oxidative stress markers ADMA and SDMA are both known to contribute significantly to the emergence of endothelial dysfunction. Increased kidney damage molecule-1 and arginein vasopressin levels suggest that these molecules may be involved in the etiology of declining renal function.

Poly(I:C)-induced maternal immune activation causes elevated self-grooming in male rat offspring: Involvement of abnormal postpartum static nursing in dam.

Introduction: Maternal immune activation (MIA) is closely related to the onset of autism-like behaviors in offspring, but the mechanism remains unclear. Maternal behaviors can influence offspring's development and behaviors, as indicated in both human and animal studies. We hypothesized that abnormal maternal behaviors in MIA dams might be other factors leading to delayed development and abnormal behaviors in offspring. Methods: To verify our hypothesis, we analyzed poly(I:C)-induced MIA dam's postpartum maternal behavior and serum levels of several hormones related to maternal behavior. Pup's developmental milestones and early social communication were recorded and evaluated in infancy. Other behavioral tests, including three-chamber test, self-grooming test, open field test, novel object recognition test, rotarod test and maximum grip test, were performed in adolescence of pups. Results: Our results showed that MIA dams exhibit abnormal static nursing behavior but normal basic care and dynamic nursing behavior. The serum levels of testosterone and arginine vasopressin in MIA dams were significantly reduced compared with control dams. The developmental milestones, including pinna detachment, incisor eruption and eye opening, were significantly delayed in MIA offspring compared with control offspring, while the weight and early social communication showed no significant differences between the two groups. Behavioral tests performed in adolescence showed that only male MIA offspring display elevated self-grooming behaviors and reduced maximum grip. Discussion: In conclusion, MIA dams display abnormal postpartum static nursing behavior concomitantly with reduced serum levels of testosterone and arginine vasopressin, possibly involving in the pathogenesis of delayed development and elevated self-grooming in male offspring. These findings hint that improving dam's postpartum maternal behavior might be a potential regime to counteract delayed development and elevated self-grooming in male MIA offspring.

Novel signalling pathways in nephrogenic syndrome of inappropriate antidiuresis: functional implication of site-specific AQP2 phosphorylation.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X-linked disease caused by gain-of-function mutations of arginine vasopressin receptor 2 (V2R). Patients with NSIAD are characterized by the inability to excrete a free water load and by inappropriately increased urinary osmolality despite very low levels of plasma vasopressin, resulting in euvolaemic hyponatraemia. To dissect the signalling downstream V2R constitutively active variants, Flp-In T-REx Madin-Darby canine kidney (FTM) cells, stably transfected with V2R mutants (R137L, R137C and F229V) and AQP2-wt or non-phosphorylatable AQP2-S269A/AQP2-S256A, were used as cellular models. All three activating V2R mutations presented constitutive plasma membrane expression of AQP2-wt and significantly higher basal water permeability. In addition, V2R-R137L/C showed significantly higher activity of Rho-associated kinase (ROCK), a serine/threonine kinase previously suggested to be involved in S269-AQP2 phosphorylation downstream of these V2R mutants. Interestingly, FTM cells expressing V2R-R137L/C mutants and AQP2-S269A showed a significant reduction in AQP2membrane abundance and a significant reduction in ROCK activity, indicating the crucial importance of S269-AQP2 phosphorylation in the gain-of-function phenotype. Conversely, V2R-R137L/C mutants retained the gain-of-function phenotype when AQP2-S256A was co-expressed. In contrast, cells expressing the F229V mutant and the non-phosphorylatable AQP2-S256A had a significant reduction in AQP2membrane abundance along with a significant reduction in basal osmotic water permeability, indicating a crucial role of Ser256 for this mutant. These data indicate that the constitutive AQP2 trafficking associated with the gain-of-function V2R-R137L/C mutants causing NSIAD is protein kinaseA independent and requires an intact Ser269 in AQP2 under the control of ROCK phosphorylation. KEY POINTS: Nephrogenic syndrome of inappropriate antidiuresis is caused by two constitutively active variant phenotypes of AVPR2, one sensitive to vaptans (V2R-F229V) and the other vaptan resistant (V2R-R137C/L). In renal cells, all three activating arginine vasopressin receptor 2 (V2R) variants display constitutive AQP2 plasma membrane expression and high basal water permeability. In cells expressing V2R-R137L/C mutants, disruption of the AQP2-S269 phosphorylation site caused the loss of the gain-of-function phenotype, which, in contrast, was retained in V2R-F229V-expressing cells. Cells expressing the V2R-F229V mutant were instead sensitive to disruption of the AQP2-S256 phosphorylation site. The serine/threonine kinase Rho-associated kinase (ROCK) was found to be involved in AQP2-S269 phosphorylation downstream of the V2R-R137L/C mutants. These findings might have clinical relevance for patients with nephrogenic syndrome of inappropriate antidiuresis.

Relationship between postpartum depression and plasma vasopressin level at 6–8 weeks postpartum: a cross-sectional study

Postpartum depression (PPD) is the most important postpartum mood disorder due to its significant effect on both the infant and family health. Arginine vasopressin (AVP) has been suggested as a hormonal agent involved in the development of depression. The purpose of this study was to investigate the relationship between the plasma concentrations of AVP and the score of Edinburgh Postnatal Depression Scale (EPDS). This cross-sectional study was conducted in 2016–2017 in Darehshahr Township, Ilam Province, Iran. In the first phase, 303 pregnant women, who were at 38 weeks, met the inclusion criteria, and were not depressed (according to their EPDS scores) were included in the study. In the 6–8 week postpartum follow-up, using the EPDS, 31 depressed individuals were diagnosed and referred to a psychiatrist for confirmation. The maternal venous blood samples of 24 depressed individuals still meeting the inclusion criteria and 66 randomly selected non-depressed subjects were obtained to measure their AVP plasma concentrations with ELISA assay. There was a significant positive relationship between plasma AVP levels and the EPDS score (P = 0.000, r = 0.658). Also the mean plasma concentration of AVP was significantly higher in the depressed group (41.35 ± 13.75 ng/ml) than in the non-depressed group (26.01 ± 7.83 ng/ml) (P < 0.001). In a multiple logistic regression model for various parameters, increased vasopressin levels were associated with increased odds of PPD (OR = 1.15, 95% CI = 1.07–1.24, P = 0.000). Furthermore, multiparity (OR = 5.45, 95% CI = 1.21–24.43, P = 0.027) and non-exclusive breastfeeding (OR = 13.06, 95% CI = 1.36–125, P = 0.026) were associated with increased odds of PPD. Maternal gender preference (having a baby of desired and desired sex) decreased the odds of PPD (OR = 0.13, 95% CI = 0.02–0.79, P = 0.027 and OR = 0.08, 95% CI = 0.01–0.5, P = 0.007). AVP seems to be a contributor to clinical PPD by affecting the hypothalamic–pituitary–adrenal (HPA) axis activity. Furthermore, primiparous women had significantly lower EPDS scores.

Activating Blood Circulation, Anti-Inflammatory and Diuretic Effects of Leonurus japonicus Extract on a Rat Model of Trauma Blood Stasis and Its Phytochemical Profiling.

Leonurus japonicus Houtt. has been traditionally used to treat many ailments. This study evaluated the activating blood circulation, anti-inflammatory, and diuretic effects of L. japonicus extract (LJ) and identified its phytochemicals. In this work, the phytochemicals in LJ were identified using liquid chromatography mass spectrometry. Rats were randomly assigned to three groups (n=8): Control group was treated with saline, while the Model group (saline) and LJ group (426 mg/kg) had induced traumatic injury. All rats were treated with once by daily oral gavage for one week. The biochemical indices and protein expression were measured. Herein, 79 constituents were identified in LJ, which were effective in elevating body weight, food consumption, water intake, and urinary excretion volume, as well as in ameliorating traumatic muscle tissues in model rats. In addition, LJ prominently decreased the contents of plasma viscosity, platelet aggregation rate, thrombin time, prothrombin time, activated partial thromboplastin time, fibrinogen, thromboxane B2 (TXB2), TXB2/6-keto-prostaglandin F1α (6-keto-PGF1α), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor 1 (PAI-1), PAI-1/tissue-type PA (t-PA), and PAI-1/u-PA, while significantly increasing antithrombin III, 6-keto-PGF1α, and t-PA contents. Furthermore, LJ notably inhibited tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, angiotensin II, antidiuretic hormone, aldosterone, aquaporin 1 (AQP1), AQP2, and AQP3 levels, and markedly elevating IL-10 and natriuretic peptide levels. Finally, LJ markedly reduced the protein expression of AQP1, AQP2, and AQP3 compared to the model group. Collectively, LJ possessed prominent activating blood circulation, anti-inflammatory, and diuretic effects, thus supporting the clinical application of L. japonicus.

Masked Randomized Trial of Epinephrine versus Vasopressin in an Ovine Model of Perinatal Cardiac Arrest.

Current neonatal resuscitation guidelines recommend the use of epinephrine for bradycardia/arrest not responding to ventilation and chest compressions. Vasopressin is a systemic vasoconstrictor and is more effective than epinephrine in postnatal piglets with cardiac arrest. There are no studies comparing vasopressin with epinephrine in newly born animal models with cardiac arrest induced by umbilical cord occlusion. Objective: To compare the effect of epinephrine and vasopressin on the incidence and time to return of spontaneous circulation (ROSC), hemodynamics, plasma drug levels, and vasoreactivity in perinatal cardiac arrest. Design/Methods: Twenty-seven term fetal lambs in cardiac arrest induced by cord occlusion were instrumented and resuscitated following randomization to epinephrine or vasopressin through a low umbilical venous catheter. Results: Eight lambs achieved ROSC prior to medication. Epinephrine achieved ROSC in 7/10 lambs by 8 ± 2 min. Vasopressin achieved ROSC in 3/9 lambs by 13 ± 6 min. Plasma vasopressin levels in nonresponders were much lower than responders after the first dose. Vasopressin caused in vivo increased pulmonary blood flow and in vitro coronary vasoconstriction. Conclusions: Vasopressin resulted in lower incidence and longer time to ROSC compared to epinephrine in a perinatal model of cardiac arrest supporting the current recommendations for exclusive use of epinephrine in neonatal resuscitation.

β-arrestin2 Mediates the Arginine Vasopressin-Induced Expression of IL-1β in Murine Hearts.

Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and this could be a factor in cardiac inflammation and fibrosis. Herein, we studied the effects of AVP on interleukin-1β (IL-1β) production and the role(s) of β-arrestin2-dependent signaling in murine heart. The levels of IL-1β mRNA and protein in adult rat cardiofibroblasts (ARCFs) was measured using quantitative PCR and ELISA, respectively. The activity of β-arrestin2 was manipulated using either pharmacologic inhibitors or through recombinant β-arrestin2 over-expression. These experiments were conducted to determine the roles of β-arrestin2 in the regulation of AVP-induced IL-1β and NLRP3 inflammasome production. The phosphorylation and activation of NF-κB induced by AVP was measured by immunoblotting. β-arrestin2 knockout (KO) mice were used to investigate whether β-arrestin2 mediated the AVP-induced production of IL-1β and NLRP3, as well as the phosphorylation of the NF-κB p65 subunitin mouse myocardium. Prism GraphPad software(version 8.0), was used for all statistical analyses. AVP induced the expression of IL-1β in a time-dependent manner in ARCFs but not in cultured adult rat cardiomyocytes (ARCMs). The inhibition of NF-κB with pyrrolidinedithiocarbamic acid (PDTC) prevented the AVP-induced phosphorylation of NF-κB and production of IL-1β and NLRP3 in ARCFs. The deletion of β-arrestin2 blocked the phosphorylation of p65 and the expression of NLRP3 and IL-1β induced by AVP in both mouse hearts and in ARCFs. AVP promotes IL-1β expression through β-arrestin2-mediated NF-κB signaling in murine heart.

Management of Hyponatremia in Heart Failure: Practical Considerations.

Hyponatremia is commonly encountered in the setting of heart failure, especially in decompensated, fluid-overloaded patients. The pathophysiology of hyponatremia in patients with heart failure is complex, including numerous mechanisms: increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system, high levels of arginine vasopressin and diuretic use. Symptoms are usually mild but hyponatremic encephalopathy can occur if there is an acute decrease in serum sodium levels. It is crucial to differentiate between dilutional hyponatremia, where free water excretion should be promoted, and depletional hyponatremia, where administration of saline is needed. An inappropriate correction of hyponatremia may lead to osmotic demyelination syndrome which can cause severe neurological symptoms. Treatment options for hyponatremia in heart failure, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. The aim of this review is to summarize the principal mechanisms involved in the occurrence of hyponatremia, to present the main guidelines for the treatment of hyponatremia, and to collect and analyze data from studies which target new treatment options, such as vaptans.

JS-HR-2: HYPERTENSION MANAGEMENT IN CKD: UPDATE FOR BETTER CARDIO-RENAL OUTCOMES

Hypertension in CKD patients is a risk factor for end-stage renal disease, cardiovascular events, and mortality. Thus, the prevention and appropriate management of hypertension in these patients are essential strategies for better cardio-renal outcomes. Recently, novel risk factors for hypertension have been reported. Circulating fibroblast growth factor 21, an endocrine hormone mainly secreted by the liver, is associated with elevated blood pressure (BP) and/or aortic stiffness with renal dysfunction. Furthermore, several promising prognostic markers for cardio-renal outcomes have been suggested. A higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in CKD patients. Higher albumin-to-creatinine ratios significantly increased the risk of first stroke or first ischemic stroke. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and mineralocorticoid receptor (MR) blockers are promising treatment options for better cardio-renal outcomes. The clinical use of SGLT2is has recently expanded to non-diabetic patients with CKD and heart failure as well as diabetic patients. SGLT2is have an antihypertensive effect, and the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a minor reduction or slight increase is observed in patients with lower baseline BP. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis, but are also associated with a low rate of hypovolemia, which is evident by the compensatory upregulation of renin and vasopressin levels. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP and better cardio-renal outcomes. MR blockers are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been launched as a treatment for CKD with type 2 diabetes. In the FIDELIO-DKD study, finerenone significantly reduced the risk of kidney and cardiovascular events in CKD and type 2 diabetes.

PS-BPB05-3: SERINE PROTEASE INHIBITION EXERTS AQUARETIC EFFECT AND DECREASES URINARY EXOSOMAL AQP2 LEVELS

Objective: Serine proteases (SPs) play pivotal roles in various physiological processes. In the kidney, it is reported that the epithelial sodium channel (ENaC) is activated via the proteolytic cleavage of α and γ subunits by SPs. We previously reported that a synthetic SP inhibitor camostat mesilate (CM) suppressed the cleavage of γENaC, thereby decreasing sodium reabsorption and blood pressure in aldosterone-infused rats. These results suggest the important roles of SPs within the kidney in the regulation of sodium homeostasis and blood pressure. Here, we aimed to identify novel physiological roles of SPs in the renal tubule and understand the mechanism of actions of SP inhibitors by administering CM into healthy rats. Design and method: Six-week-old male Sprague-Dawley rats were divided into control and CM groups. CM group rats were subcutaneously implanted with sustained-release pellets of CM (14 mg/day). After 24 h urine collection was performed, rats were sacrificed at day 7 to obtain blood and kidney samples. Urine volume was measured during the experimental period, and blood and urinary electrolytes, blood vasopressin, and renal tissue osmolality were measured. Protein expression of SPs and aquaporin-2 (AQP2) was analyzed by Western blotting. Results: CM significantly increased urine volume by approximately two-fold throughout the experimental period [urine volume (mL/day): control, 15.5 ± 2.4; CM, 30.6 ± 5.8], in a urinary sodium and osmolyte excretion-independent manner, which indicated that free water excretion had occurred. The vasopressin, potassium, and calcium levels in the blood and osmolality in the inner medulla, which affect free water reabsorption in the renal tubule, remained unchanged after CM administration. CM decreased urinary exosomal AQP2 excretion, suggesting that the AQP2 activity was suppressed in the collecting duct. These changes were reversed by the infusion of desmopressin. Such water diuretic action caused by CM was independent of its action on prostasin and TMPRSS4, which are serine proteases associated with sodium and water homeostasis, respectively. Conclusion: Our results revealed the association of SP inhibition with free water diuresis in the kidney and demonstrated that CM administration resulted in the downregulation of AQP2. The current findings suggest that SP inhibitors could become a new class of aquaretic drugs.

PS-BPB10-1: INVOLVEMENT OF RENAL TUBULAR NFAT5 IN THE REGULATION OF BLOOD PRESSURE AND BODY FLUID VOLUME

Objective: Nuclear factor of activated T-cells 5 (NFAT5) is an osmoresponsive transcription factor that activates osmoprotective genes to protect cells against hypertonicity. Renal tubular cell-specific NFAT5 knockout (KO) mice have been shown to exhibit polyuria, hypernatremia, low urinary sodium excretion, and increased expression of the epithelial sodium channel (ENaC) in the kidney. In the present study, regulation of blood pressure (BP) as well as that of body fluid volume were examined in the wild type (WT) mice and NFAT5 KO mice. Methods: The BP of KO mice and WT mice was measured using radiotelemetry method. The mice were fed with regular salt diet (RSD, 0.3% NaCl chow) or high salt diet (HSD, 8% NaCl chow) followed by the treatment with amiloride, an ENaC blocker. To assess body fluid volume, the plasma renin activity (PRA) and the plasma aldosterone concentration (PAC) were measured at the condition of RSD and HSD, together with plasma arginine vasopressin (AVP) and hematocrit (Ht) levels. Results: Compared to WT mice, the mean BP was significantly higher in KO mice both at the condition with RSD and that with HSD in dark period, but not in light period. Treatment with amiloride significantly decreased the mean BP in KO mice with HSD to the level of WT mice with HSD in dark period. PRA, PAC, and AVP levels were not significantly different between in WT and KO mice with RSD. HSD significantly decreased PRA and PAC and tended to increase the AVP level both in WT and KO mice. The Ht level was significantly lower in KO mice than in WT mice regardless of RSD or HSD (WT with RSD, 42.6 ± 0.5%; WT with HSD, 42.8 ± 0.6%; KO with RSD, 38.3 ± 0.4%; KO with HSD, 39.0 ± 0.4%, n = 4). Conclusions: The results suggest that the renal tubular cell-specific NFAT5 KO mice exhibit excess body fluid retention induced by sodium reabsorption through ENaC, leading to salt-sensitive hypertension. Such phenotypes seem to be independent of the systemic renin-angiotensin-aldosterone and AVP systems. Renal tubular NFAT5 could integrate urine concentration and sodium reabsorption in the kidney, thus preventing salt-dependent hypertension.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

Fructose might be a clue to the origin of preeclampsia insights from nature and evolution.

Preeclampsia is a hypertensive disorder of pregnancy and is due to abnormal placentation. The pathogenesis remains unclear. Fructose is biologically distinct from glucose and has a critical role in fetal growth in early pregnancy. Many species, including humans, produce fructose in their placenta during the first trimester to assist fetal growth and survival during a time when hypoxia is significant. Fructose is preferred over glucose in hypoxic tissues, and in the developing fetus, fructose has a critical role in stimulating the production of nucleic acids, lipids and glycosaminoglycans. Fructose production normally decreases significantly following the establishment of maternal-fetal circulation following placentation. However, if there is impaired placentation, local hypoxia will continue to drive fructose production. Excessive fructose metabolism drives endothelial dysfunction, oxidative stress, elevated blood pressure, insulin resistance, fatty liver, and a rise in uric acid and vasopressin levels, all of which are features of the preeclamptic state. In addition to fructose production, dietary fructose, for example, from soft drinks, would be additive and has been reported to be a strong independent risk factor for preeclampsia. Uric acid-associated endothelial dysfunction disturbs the invasion of the spiral artery, leading to placental ischemia and further placental hypoxia. Here, we summarize the previous literature regarding the physiological and pathological roles of fructose in pregnancy and propose studies to further investigate the pathogenesis of preeclampsia. Fructose might be a Clue to the Origin of Preeclampsia Insights from Nature and Evolution Preeclampsia is a hypertensive disorder of pregnancy. The pathogenesis remains unclear. Fructose has a critical role in fetal growth in early pregnancy, and might be a key role to developing preeclampsia. Here, we summarize the previous literatures regarding the physiological andpathological roles of fructose in pregnancy to propose studies to further investigate the pathogenesis of preeclampsia.

Desmopressin responding female nephrogenic diabetes insipidus: a case report

Nephrogenic diabetes insipidus, decreased ability to concentrate urine, with production of large amounts of urine, is caused by the refractory response of renal tubules to the action of antidiuretic hormone. This rare disorder, known as X-linked nephrogenic diabetes insipidus, is caused by a mutation in the arginine vasopressin receptor 2 gene. Because it is hereditary, most patients are male. This report highlights a case of nephrogenic diabetes insipidus in a 3-year 5-month-old female; upon presentation to the hospital, her symptoms included frequent urination and consumption of a significant amount of water, which had begun 2 years ago. The results of blood tests showed increased levels of serum antidiuretic hormone, and sellar magnetic resonance imaging showed no abnormality. The results of the water restriction test and the desmopressin administration test confirmed the diagnosis of nephrogenic diabetes insipidus showing a partial response to desmopressin. The results of genetic testing indicated the presence of an arginine vasopressin receptor 2 mutation, a heterozygous missense mutation (p.Val88Met), suggesting inheritance of X-linked nephrogenic diabetes insipidus. This report describes a significant case of symptomatic X-linked nephrogenic diabetes insipidus in a female patient who showed a partial response to desmopressin.