Predictive modeling of arginine vasopressin deficiency after transsphenoidal pituitary adenoma resection by using multiple machine learning algorithms.

This study aimed to predict arginine vasopressin deficiency (AVP-D) following transsphenoidal pituitary adenoma surgery using machine learning algorithms. We reviewed 452 cases from December 2013 to December 2023, analyzing clinical and imaging data. Key predictors of AVP-D included sex, tumor height, preoperative and postoperative changes in sellar diaphragm height and pituitary stalk length, preoperative ACTH levels, changes in ACTH levels, and preoperative cortisol levels. Six machine learning algorithms were tested: logistic regression (LR), support vector classification (SVC), random forest (RF), decision tree (DT), k-nearest neighbors (KNN), and extreme gradient boosting (XGBoost). After cross-validation and parameter optimization, the random forest model demonstrated the highest performance, with an accuracy (ACC) of 0.882 and an AUC of 0.96. The decision tree model followed, achieving an accuracy of 0.843 and an AUC of 0.95. Other models showed lower performance: LR had an ACC of 0.522 and an AUC of 0.54; SVC had an ACC of 0.647 and an AUC of 0.67; KNN achieved an ACC of 0.64 and an AUC of 0.70; and XGBoost had an ACC of 0.794 and an AUC of 0.91. The study found that a shorter preoperative pituitary stalk length, significant intraoperative stretching, and lower preoperative ACTH and cortisol levels were associated with a higher likelihood of developing AVP-D post-surgery.

Arginine vasopressin deficiency onset after COVID-19 vaccination with positive anti-rabphilin-3A antibodies: a case report and literature review.

BACKGROUND: Arginine vasopressin deficiency (AVP-D) can occur due to various conditions, so clarifying its cause is important for deciding treatment strategy. Although several cases of AVP-D following coronavirus disease 2019(COVID-19) infection or COVID-19 vaccination have been reported, the diagnosis of the underlying disease has not been reported in most cases. CASE PRESENTATION: A 75-year-old woman who presented with polydipsia and polyuria 9 weeks after contracting COVID-19 and 5 weeks after receiving the SARS-CoV-2 vaccination, leading to the final diagnosis of AVP-D 8 months after the first appearance of symptoms. Interestingly, pituitary magnetic resonance imaging (MRI) still revealed stalk enlargement frequently observed in patients with SARS-CoV-2 vaccination-induced AVP-D. Although this finding could not rule out any malignancies, we additionally measured anti-rabphilin-3A antibodies, a known marker for lymphocytic infundibulo-neurohypophysitis (LINH), and found that the results were positive, strongly suggesting LINH as the cause of this disease. Thus, we avoided pituitary biopsy. At the follow-up MRI conducted 12 months after the initial consultation, enlargement of the pituitary stalk was still observed. CONCLUSION: We experienced a case with LINH probably induced by SARS-CoV-2 vaccination. In SARS-CoV-2 vaccination-related LINH, unlike typical LINH, there is a possibility of persistent pituitary stalk enlargement on MRI images for an extended period, posing challenges in differential diagnosis from other conditions. Pituitary stalk enlargement and positive anti-rabphilin-3A antibodies may help in the diagnosis of AVP-D induced by SARS-CoV-2 vaccination.

Assessment of exercise-induced dehydration in underhydrated athletes: Which method shows the most promise?

BACKGROUND & AIMS: Athletes are commonly exposed to exercise-induced dehydration. However, the best method to detect dehydration under this circumstance is not clear. This study aimed to analyze pre- and post-dehydration measurements of biomarkers, including saliva osmolality (SOsm), urine osmolality (UOsm), urine-specific gravity (USG), urine color (Ucolor), serum osmolality (SeOsm), serum arginine vasopressin (AVP), serum sodium (Na+), and thirst sensation in underhydrated athletes, using the body mass loss (BML) as the reference method. METHODS: In this clinical trial (NCT05380089), a total of 38 athletes (17 females) with a regular low water intake (<35 mL/kg/day) were submitted to exercise-induced dehydration with a heat index of 29.8 ± 3.1 °C and an individualized running intensity (80-90% of first ventilatory threshold). RESULTS: ROC curve analysis revealed significant discriminative abilities of SOsm, with AUC values of 0.76 at 1.5% BML, 0.75 at 1.75% BML, and 0.87 at 2% BML, while Na+ and SeOsm showed the highest AUC of 0.87 and 0.91 at 2% BML, respectively. SOsm showed high sensitivity at 1.5% of BML, while SeOsm and Na+ demonstrated high sensitivity at 2% of BML. CONCLUSION: This study highlights SOsm as a potential indicator of hydration status across different levels of BML. Additionally, Na+ and SeOsm emerged as accurate dehydration predictors at 1.75% and 2% of BML. Notably, the accuracy of urinary indices and thirst sensation for detecting hydration may be limited.

Is renal dysfunction amplified in an arginine vasopressin induced rat model of preeclampsia?

Renal dysfunction is important in preeclampsia (PE) pathophysiology and has not been fully explored in the arginine vasopressin (AVP) rat model of PE. This study aimed to determine kidney toxicity associated with this model. Female Sprague Dawley rats (n = 24) were subcutaneously infused with AVP or saline for 18 days. Urine samples (GD8, 14 and 18) were used to determine the levels of albumin, VEGF-A, clusterin, NGAL/Lipocalin-2, KIM-1, cystatin C, TIMP-1, ß2M and OPN via Multiplex ELISAs. Albumin, and NGAL/lipocalin-2 were significantly elevated in the PAVP vs PS group on GD14 and GD18 (p < 0.001) respectively. VEGF-A significantly decreased in the pregnant vs non-pregnant groups on GD14 and 18 (p < 0.001). Clusterin (p < 0.001) and OPN (p < 0.05) were significantly higher in the PAVP vs PS group on GD18. Cystatin C and KIM-1 are significantly upregulated in the PAVP vs PS groups throughout gestation (p < 0.05). ß2M is significantly elevated in the PAVP vs PS group on GD14 and 18 (p < 0.05). AVP elevated the urinary levels of the kidney injury biomarkers and replicated the renal dysfunction associated with PE development. Our findings confirm the potential applications of this model in studying the mechanisms underlying renal damage in PE.

Hypopituitarism with secondary adrenocortical insufficiency and arginine vasopressin deficiency due to hypophysitis after COVID-19 vaccination: a case report.

BACKGROUND: Although vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported. CASE PRESENTATION: An 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 µg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 µIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient's disease course was stable with continued thyroid and adrenal corticosteroid supplementation. CONCLUSIONS: Herein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Factors associated with vasoplegic shock in the postoperative period of cardiac surgery and influence on morbidity and mortality of the use of arginine vasopressin as rescue therapy.

OBJECTIVES: Analyzing associated factors with vasoplegic shock in the postoperative period of Cardiac Surgery. Analyzing the influence of vasopressin as rescue therapy to first-line treatment with norepinephrine. DESIGN: Cohort, prospective and observational study. SETTING: Main hospital Postoperative Cardiac ICU. PATIENTS: Patients undergoing cardiac surgery with subsequent ICU admission from January 2021 to December 2022. INTERVENTIONS: Record of presurgical, perioperative and ICU discharge clinical variables. MAIN VARIABLES OF INTEREST: chronic treatment, presence of vasoplegic shock, need for vasopressin, cardiopulmonary bypass time, mortality. RESULTS: 773 patients met the inclusion criteria. The average age was 67.3, with predominance of males (65.7%). Post-CPB vasoplegia was documented in 94 patients (12.2%). In multivariate analysis, vasoplegia was associated with age, female sex, presurgical creatinine levels, cardiopulmonary bypass time, lactate level upon admission to the ICU, and need for prothrombin complex transfusion. Of the patients who developed vasoplegia, 18 (19%) required rescue vasopressin, associated with pre-surgical intake of ACEIs/ARBs, worse Euroscore score and longer cardiopulmonary bypass time. Refractory vasoplegia with vasopressin requirement was associated with increased morbidity and mortality. CONCLUSIONS: Postcardiopulmonary bypass vasoplegia is associated with increased mortality and morbidity. Shortening cardiopulmonary bypass times and minimizing products blood transfusion could reduce its development. Removing ACEIs and ARBs prior to surgery could reduce the incidence of refractory vasoplegia requiring rescue with vasopressin. The first-line treatment is norepinephrine and rescue treatment with VSP is a good choice in refractory situations. The first-line treatment of this syndrome is norepinephrine, although rescue with vasopressin is a good complement in refractory situations.

Hypothalamic vasopressin sex differentiation is observed by embryonic day 15 in mice and is disrupted by the xenoestrogen bisphenol A.

Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVPPVN) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth ( embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVPPVN neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVPPVN neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP+ by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVPPVN neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVPPVN neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVPPVN sex differentiation, which is impacted by prenatal BPA exposure.

A cAMP-biosensor-based assay for measuring plasma arginine-vasopressin levels.

Arginine-vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations via the vasopressin V2 receptor (V2R). Plasma AVP is a valuable biomarker for the diagnosis of central diabetes insipidus (CDI) and is commonly measured using radioimmunoassay (RIA). However, RIA has several drawbacks, including a long hands-on time, complex procedures, and handling of radioisotopes with special equipment and facilities. In this study, we developed a bioassay to measure plasma AVP levels using HEK293 cells expressing an engineered V2R and a cAMP biosensor. To achieve high sensitivity, we screened V2R orthologs from 11 various mammalian species and found that the platypus V2R (pV2R) responded to AVP with approximately six-fold higher sensitivity than that observed by the human V2R. Furthermore, to reduce cross-reactivity with desmopressin (DDAVP), a V2R agonist used for CDI treatment, we introduced a previously described point mutation into pV2R, yielding an approximately 20-fold reduction of responsiveness to DDAVP while maintaining responsiveness to AVP. Finally, a comparison of plasma samples from 12 healthy individuals demonstrated a strong correlation (Pearson's correlation value: 0.90) between our bioassay and RIA. Overall, our assay offers a more rapid and convenient method for quantifying plasma AVP concentrations than existing techniques.

Sex differences in responses to aggressive encounters among California mice.

Despite how widespread female aggression is across the animal kingdom, there remains much unknown about its neuroendocrine mechanisms, especially in females that engage in aggression outside the peripartum period. Although the impact of aggressive experience on steroid hormone responses have been described, little is known about the impact of these experiences on female behavior or the subsequent neuropeptide responses to performing aggression. In this study, we compared behavioral responses in both male and female adult California mice based on if they had 0, 1, or 3 aggressive encounters using a resident intruder paradigm. We measured how arginine vasopressin and oxytocin cells in the paraventricular nucleus responded to aggression using c-fos immunohistochemistry. We saw that both sexes disengaged from intruders with repeated aggressive encounters, but that on the final day of testing females were more likely to freeze when they encountered intruders compared to no aggression controls - which was not significant in males. Finally, we saw that percent of arginine vasopressin and c-fos co-localizations in the posterior region of the paraventricular nucleus increased in males who fought compared to no aggression controls. No difference was observed in females. Overall, there is evidence that engaging in aggression induces stress responses in both sexes, and that females may be more sensitive to the effects of fighting.

Circadian rhythm mechanism in the suprachiasmatic nucleus and its relation to the olfactory system.

Animals need sleep, and the suprachiasmatic nucleus, the center of the circadian rhythm, plays an important role in determining the timing of sleep. The main input to the suprachiasmatic nucleus is the retinohypothalamic tract, with additional inputs from the intergeniculate leaflet pathway, the serotonergic afferent from the raphe, and other hypothalamic regions. Within the suprachiasmatic nucleus, two of the major subtypes are vasoactive intestinal polypeptide (VIP)-positive neurons and arginine-vasopressin (AVP)-positive neurons. VIP neurons are important for light entrainment and synchronization of suprachiasmatic nucleus neurons, whereas AVP neurons are important for circadian period determination. Output targets of the suprachiasmatic nucleus include the hypothalamus (subparaventricular zone, paraventricular hypothalamic nucleus, preoptic area, and medial hypothalamus), the thalamus (paraventricular thalamic nuclei), and lateral septum. The suprachiasmatic nucleus also sends information through several brain regions to the pineal gland. The olfactory bulb is thought to be able to generate a circadian rhythm without the suprachiasmatic nucleus. Some reports indicate that circadian rhythms of the olfactory bulb and olfactory cortex exist in the absence of the suprachiasmatic nucleus, but another report claims the influence of the suprachiasmatic nucleus. The regulation of circadian rhythms by sensory inputs other than light stimuli, including olfaction, has not been well studied and further progress is expected.

Social regulation of arginine vasopressin and oxytocin systems in a wild group-living fish.

The neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) are key regulators of social behaviour across vertebrates. However, much of our understanding of how these neuropeptide systems interact with social behaviour is centred around laboratory studies which fail to capture the social and physiological challenges of living in the wild. To evaluate relationships between these neuropeptide systems and social behaviour in the wild, we studied social groups of the cichlid fish Neolamprologus pulcher in Lake Tanganyika, Africa. We first used SCUBA to observe the behaviour of focal group members and then measured transcript abundance of key components of the AVP and OXT systems across different brain regions. While AVP is often associated with male-typical behaviours, we found that dominant females had higher expression of avp and its receptor (avpr1a2) in the preoptic area of the brain compared to either dominant males or subordinates of either sex. Dominant females also generally had the highest levels of leucyl-cystinyl aminopeptidase (lnpep)-which inactivates AVP and OXT-throughout the brain, potentially indicating greater overall activity (i.e., production, release, and turnover) of the AVP system in dominant females. Expression of OXT and its receptors did not differ across social ranks. However, dominant males that visited the brood chamber more often had lower preoptic expression of OXT receptor a (oxtra) suggesting a negative relationship between OXT signalling and parental care in males of this species. Overall, these results advance our understanding of the relationships between complex social behaviours and neuroendocrine systems under natural settings.

Uso de vasopresina en el postoperatorio de cirugía de Fontan: inferencias sobre morbimortalidad / Vasopressin use in postoperative Fontan surgery: implications for morbidity and mortality

Introducción: Se ha postulado que el uso de vasopresina tendría efectos beneficiosos en el postoperatorio de cirugía cardiovascular. Objetivo: Evaluar la respuesta a la vasopresina en el postoperatorio (POP) de cirugía de Fontan de nuestra población. Métodos: Estudio de casos y controles anidados en una cohorte retrospectiva. Se incluyeron pacientes con cirugía de Fontan entre 2014 y 2019. Se registraron variables demográficas, datos del cateterismo pre-Fontan, días de asistencia respiratoria mecánica (ARM), necesidad de inotrópicos, diuréticos, diálisis, dieta hipograsa, octreotide, sildenafil y nutrición parenteral total (NPT); balance de fluidos al primer y segundo día POP, necesidad de cateterismo en el POP, días de permanencia de tubo pleural, días de internación, necesidad de reinternación y mortalidad. Se compararon los grupos con y sin vasopresina utilizando la prueba de Mann- Whitney-Wilcoxon test. Se consideró significativa una p < 0.05. Resultados: Del total analizado, 35 pacientes recibieron vasopresina. En el grupo control fueron 58 pacientes con características similares de gravedad sin vasopresina. No se encontraron diferencias en la evolución postoperatoria entre ambos grupos. El grupo con vasopresina recibió en mayor proporción dieta hipograsa. Conclusiones: En nuestra serie el uso de vasopresina no marcó diferencias significativas en términos de morbimortalidad con relación al grupo control (AU)

Introduction: The use of vasopressin has been suggested to have beneficial effects in the postoperative period after cardiovascular surgery. Objective: To evaluate the response to vasopressin in the postoperative period (POP) of Fontan surgery in our population. Methods: Nested case-control study in a retrospective cohort. Patients who underwent Fontan surgery between 2014 and 2019 were included. Demographic variables, pre-Fontan catheterization data, days of mechanical ventilation (MRA), need for inotropics, diuretics, dialysis, low-fat diet, octreotide, sildenafil and total parenteral nutrition (TPN); fluid balance at first and second day POP, need for catheterization at POP, duration of chest tube drainage, days of hospitalization, need for readmission, and mortality were recorded. Groups with and without vasopressin were compared using the Mann-Whitney- Wilcoxon test. A p < 0.05 was considered significant. Results: Of all patients analyzed, 35 received vasopressin. The control group consisted of 58 patients with similar severity characteristics who did not receive vasopressin. No differences were found in the postoperative outcome between the two groups. The vasopressin group received a higher proportion of low-fat diet. Conclusions: In our series the use of vasopressin did not show significant differences in terms of morbidity and mortality compared to the control group (AU)

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation.

INTRODUCTION: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. METHODS: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). RESULTS: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. DISCUSSION: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

Arginine vasopressin regulates the renal Na+-Cl- and Na+-K+-Cl- cotransporters through with-no-lysine kinase 4 and inhibitor 1 phosphorylation.

Vasopressin regulates water homeostasis via the V2 receptor in the kidney at least in part through protein kinase A (PKA) activation. Vasopressin, through an unknown pathway, upregulates the activity and phosphorylation of Na+-Cl- cotransporter (NCC) and Na+-K+-2Cl- cotransporter 2 (NKCC2) by Ste20-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1), which are regulated by the with-no-lysine kinase (WNK) family. Phosphorylation of WNK4 at PKA consensus motifs may be involved. Inhibitor 1 (I1), a protein phosphatase 1 (PP1) inhibitor, may also play a role. In human embryonic kidney (HEK)-293 cells, we assessed the phosphorylation of WNK4, SPAK, NCC, or NKCC2 in response to forskolin or desmopressin. WNK4 and cotransporter phosphorylation were studied in desmopressin-infused WNK4-/- mice and in tubule suspensions. In HEK-293 cells, only wild-type WNK4 but not WNK1, WNK3, or a WNK4 mutant lacking PKA phosphorylation motifs could upregulate SPAK or cotransporter phosphorylation in response to forskolin or desmopressin. I1 transfection maximized SPAK phosphorylation in response to forskolin in the presence of WNK4 but not of mutant WNK4 lacking PP1 regulation. We observed direct PP1 regulation of NKCC2 dephosphorylation but not of NCC or SPAK in the absence of WNK4. WNK4-/- mice with desmopressin treatment did not increase SPAK/OSR1, NCC, or NKCC2 phosphorylation. In stimulated tubule suspensions from WNK4-/- mice, upregulation of pNKCC2 was reduced, whereas upregulation of SPAK phosphorylation was absent. These findings suggest that WNK4 is a central node in which kinase and phosphatase signaling converge to connect cAMP signaling to the SPAK/OSR1-NCC/NKCC2 pathway.NEW & NOTEWORTHY With-no-lysine kinases regulate the phosphorylation and activity of the Na+-Cl- and Na+-K+-2Cl- cotransporters. This pathway is modulated by arginine vasopressin (AVP). However, the link between AVP and WNK signaling remains unknown. Here, we show that AVP activates WNK4 through increased phosphorylation at putative protein kinase A-regulated sites and decreases its dephosphorylation by protein phosphatase 1. This work increases our understanding of the signaling pathways mediating AVP actions in the kidney.

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore, arginine vasopressin, which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low versus high [Na+], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9-mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.

A novel antidiuretic hormone governs tumour-induced renal dysfunction.

Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules-an excretory organ that is equivalent to renal tubules4-to activate nitric oxide synthase-cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour-renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.

Arginine vasopressin injection rescues delayed oviposition in cyp19a1b-/- mutant female zebrafish.

In zebrafish, estrogens produced in the ovaries via Cyp19a1a activity are required for both sexual differentiation of the ovary during early development as well as maintenance of the ovarian state during adulthood. The importance of Cyp19a1b that is highly expressed in the brain for female reproduction is still under study. We previously reported that female cyp19a1b -/- mutant zebrafish have significantly lower brain estradiol levels and impaired spawning behavior characterized by an increased latency to oviposition during dyadic sexual behavior encounters. In the current study, we provide evidence that the delayed oviposition in female cyp19a1b -/- mutants is linked to impaired arginine vasopressin (Avp) signaling. Droplet digital PCR experiments revealed that levels of the estrogen receptors, avp, and oxytocin (oxt) are lower in the hypothalamus of mutant females compared to wildtype fish. We then used acute intraperitoneal injections of Avp and Oxt, along with mixtures of their respective receptor antagonists, to determine that Avp can uniquely rescue the delayed oviposition in female cyp19a1b -/- mutants. Using immunohistochemistry, we demonstrated that Cyp19a1b-expressing radial glial cell (RGC) fibers surround and are in contact with Avp-immunopositive neurons in the preoptic areas of the brain. This could provide the neuroanatomical proximity for RGC-derived estrogens to diffuse to and activate estrogen receptors and regulate avp expression levels. Together these findings identify a positive link between Cyp19a1b and Avp for female zebrafish sexual behavior. They also suggest that the female cyp19a1b -/- mutant behavioral phenotype is likely a consequence of impaired processing of Avp-dependent social cues important for mate identification and assessment.

Copeptin analysis in endocrine disorders.

Copeptin is cleaved from the same precursor as arginine vasopressin and is released in equimolar amounts with arginine vasopressin from the posterior pituitary in response to the same stimuli. Its level of stability in the blood, quick and simple analysis, and ease of automation make it much easier to analyze than arginine vasopressin, thereby offering a suitable alternative to measuring arginine vasopressin in endocrine disorders. Research has demonstrated the suitability of copeptin in adults for the differentiation of arginine vasopressin resistance and arginine vasopressin deficiency from primary polydipsia, in addition to the early identification of arginine vasopressin deficiency following pituitary surgery; however, further research is still required in the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and the pediatric population.

Neurohypophysial and paracrine vasopressinergic signaling regulates aquaporin trafficking to hydrate marine teleost oocytes.

The dual aquaporin (Aqp1ab1/Aqp1ab2)-mediated hydration of marine teleost eggs, which occurs during oocyte meiosis resumption (maturation), is considered a key adaptation underpinning their evolutionary success in the oceans. However, the endocrine signals controlling this mechanism are almost unknown. Here, we investigated whether the nonapeptides arginine vasopressin (Avp, formerly vasotocin) and oxytocin (Oxt, formerly isotocin) are involved in marine teleost oocyte hydration using the gilthead seabream (Sparus aurata) as a model. We show that concomitant with an increased systemic production of Avp and Oxt, the nonapeptides are also produced and accumulated locally in the ovarian follicles during oocyte maturation and hydration. Functional characterization of representative Avp and Oxt receptor subtypes indicates that Avpr1aa and Oxtrb, expressed in the postvitellogenic oocyte, activate phospholipase C and protein kinase C pathways, while Avpr2aa, which is highly expressed in the oocyte and in the follicular theca and granulosa cells, activates the cAMP-protein kinase A (PKA) cascade. Using ex vivo, in vitro and mutagenesis approaches, we determined that Avpr2aa plays a major role in the PKA-mediated phosphorylation of the aquaporin subdomains driving membrane insertion of Aqp1ab2 in the theca and granulosa cells, and of Aqp1ab1 and Aqp1ab2 in the distal and proximal regions of the oocyte microvilli, respectively. The data further indicate that luteinizing hormone, which surges during oocyte maturation, induces the synthesis of Avp in the granulosa cells via progestin production and the nuclear progestin receptor. Collectively, our data suggest that both the neurohypophysial and paracrine vasopressinergic systems integrate to differentially regulate the trafficking of the Aqp1ab-type paralogs via a common Avp-Avpr2aa-PKA pathway to avoid competitive occupancy of the same plasma membrane space and maximize water influx during oocyte hydration.

Argipressin for prevention of blood loss during liver resection: a study protocol for a randomised, placebo-controlled, double-blinded trial (ARG-01).

INTRODUCTION: Liver resection carries a high risk for extensive bleeding and need for blood transfusions, which is associated with significant negative impact on outcome. In malignant disease, the most common indication for surgery, it also includes increased risk for recurrence of cancer. Argipressin decreases liver and portal blood flow and may have the potential to reduce bleeding during liver surgery, although this has not been explored. METHOD AND ANALYSIS: ARG-01 is a prospective, randomised, placebo-controlled, double-blinded study on 248 patients undergoing liver resection at Sahlgrenska University Hospital, Sweden. Patients will be randomised to one of two parallel groups, infusion of argipressin or normal saline administered peroperatively. The primary endpoint is peroperative blood loss. Secondary outcomes include need for blood transfusion, perioperative variables, length of hospital stay, the inflammatory response, organ damage markers and complications at 30 days. ETHICS AND DISSEMINATION: The study is enrolling patients since March 2022. The trial is approved by the Swedish Ethical Review Authority (Dnr 2021-03557) and the Swedish Medical Product Agency (Dnr 5.1-2021-90115). Results will be announced at scientific meetings and in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05293041 and EudraCT, 2021-001806-32.