Vasopressin Receptor Research Articles

Electrochemical Behavior and Determination of Tolvaptan Using Glassy Carbon and Boron-Doped Diamond Electrodes

Tolvaptan (TOL), a vasopressin V2 receptor antagonists drug, is used to treat hyponatremia in people with heart failure. Herein, we report for the first time the electrochemical behavior of TOL and its oxidation metabolite TOL-oxo on glassy carbon and boron-doped diamond electrodes (GCE, BDDE) by cyclic voltammetry (CV). For both molecules, two-electron irreversible oxidation was observed in 0.5 M H2SO4, while single-electron irreversible oxidation occurred at pH 7.0. A sensitive and rapid electroanalytical technique for the detection of TOL has been developed, based on differential pulse voltammetry (DPV). Linearity was obtained with GCE within a concentration range between 1–1000 μM, using anodic currents appearing around 1397 mV. For BDDE, the concentration range was 8–1000 μM using anodic currents around 1490 mV.

Poly(ADP-ribose) polymerase-1 affects vasopressin-mediated AQP2 expression in collecting duct cells of the kidney.

Poly(ADP-ribosyl)ation (PARylation), as a posttranslational modification mediated by poly(ADP-ribose) polymerases (PARPs) catalyzing the transfer of ADP-ribose from NAD+ molecules to acceptor proteins, involves a number of cellular processes. As mice lacking the PARP-1 gene (Parp1) produce more urine, we investigated the role of PARP-1, the most prevalent member of the PARP family, in the vasopressin-responsive expression of aquaporin-2 (AQP2). In biotin-conjugated nicotinamide adenine dinucleotide (biotin-NAD+) pulldown and immunoprecipitation assays of poly(ADP)-ribose in mpkCCDc14 cells, immunoblots demonstrated that 1-deamino-8-D-arginine vasopressin (dDAVP) induced the PARylation of total proteins, associated with an increase in the cleavage of PARP-1 and cleaved caspase-3 expression. By inhibiting PARP-1 with siRNA, the abundance of dDAVP-induced AQP2 mRNA and protein was significantly diminished. In contrast, despite a substantial decrease in PARylation, the PARP-1 inhibitor (PJ34) had no effect on the dDAVP-induced regulation of AQP2 expression. The findings suggest that PARP-1 protein expression itself, and not PARP-1-mediated PARylation, is necessary for dDAVP-regulated AQP2 expression. Bioinformatic analysis revealed that 408 proteins interact with PARP-1 in the collecting duct (CD) cells of the kidney. Among them, the signaling pathway of the vasopressin V2 receptor was identified for 49 proteins. In particular, β-catenin, which is phosphorylated at Ser552 by dDAVP, was identified as the PARP-1-interacting protein. A significant decrease of β-catenin phosphorylation (Ser552) in response to dDAVP was associated with siRNA-mediated PARP-1 knockdown. Taken together, PARP-1 is likely to play a role in vasopressin-induced AQP2 expression by interacting with β-catenin in renal CD cells.NEW & NOTEWORTHY The poly(ADP-ribose) polymerase (PARP) family catalyzes poly(ADP-ribosylation) (PARylation), which is one of the posttranslational modifications of largely undetermined physiological significance. This study investigated the role of PARP-1, the most prevalent member of the PARP family, in the vasopressin-responsive expression of aquaporin-2 (AQP2). The results demonstrated that PARP-1 protein expression itself, and not PARP-1-mediated PARylation, is necessary for dDAVP-regulated AQP2 expression. β-Catenin, which is phosphorylated at Ser552 by dDAVP, was identified as the PARP-1-interacting protein.

Association of OXTR, AVPR1a, LNPEP, and CD38 Genes' Expression with the Clinical Presentation of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social interactions, communication, and behavior. Although the predominant genetic predisposition to ASD seems beyond doubt, its exact nature remains unclear. In the context of social cognition disorders and the basis of ASD, the oxytocinergic and vasopresynergic systems arouse great interest among researchers. The aim of the present study was to analyze gene expression levels for oxytocin and vasopressin receptors, as well as CD38 protein and oxytocinase, in the context of the clinical picture of autism spectrum disorders. The study included 90 people, of whom 63 were diagnosed with ASD based on anamnesis, mental status testing, and the ADOS-2 protocol. The results obtained in the presented study indicate that the balance between the levels of expression of the CD38 gene and the oxytocinase gene plays a key role in the risk and clinical presentation of ASD. In a hypothetical scenario, an imbalance in the expression of CD38 and LNPEP could potentially lead to alterations in the concentrations of oxytocin and vasopressin. At the same time, the most frequently studied genes-AVPR1a and OXTR-seem to be at best of marginal importance for the risk of ASD.

Neonatal AVPR1a Methylation and In-Utero Exposure to Maternal Smoking.

(1) Introduction: Epigenetic changes have been proposed as a biologic link between in-utero exposure to maternal smoking and health outcomes. Therefore, we examined if in-utero exposure to maternal smoking was associated with infant DNA methylation (DNAm) of cytosine-phosphate-guanine dinucleotides (CpG sites) in the arginine vasopressin receptor 1A AVPR1a gene. The AVPR1a gene encodes a receptor that interacts with the arginine vasopressin hormone and may influence physiological stress regulation, blood pressure, and child development. (2) Methods: Fifty-two infants were included in this cohort study. Multivariable linear models were used to examine the effect of in-utero exposure to maternal smoking on the mean DNAm of CpG sites located at AVPR1a. (3) Results: After adjusting the model for substance use, infants with in-utero exposure to maternal smoking had a reduction in DNAm at AVPR1a CpG sites by -0.02 (95% CI -0.03, -0.01) at one month of age. In conclusion, in-utero exposure to tobacco smoke can lead to differential patterns of DNAm of AVPR1a among infants. Conclusions: Future studies are needed to identify how gene expression in response to early environmental exposures contributes to health outcomes.

FRI354 Therapeutic Potential Of Oxcarbazepine In Central Diabetes Insipidus

Abstract Disclosure: S. Pittampalli: None. V. Pattan: None. D. Das: None. U. Munasinghe: None. Introduction: Postoperative central Diabetes insipidus is usually transient but can be persistent. Persistent central Diabetes insipidus is prone to dose fluctuations in clinically unstable patients, especially when concomitant medications influence sodium and water homeostasis. Clinical Case: A 24-year-old female with headache and confusion had sellar and suprasellar mass of 6 cm x 4 cm with moderate to severe hydrocephalus and underwent Right craniotomy with debulking of the mass and pathology showed pilocytic astrocytoma. Postoperative course was complicated by short-term memory loss, right-sided weakness, adrenal insufficiency, and visual impairment. Repeat imaging showed increased size of suprasellar mass consequently requiring a transnasal transphenoidal resection. Post-operative neurological worsening was noted along with diffuse subarachnoid/ intraventricular hemorrhage with intraparenchymal hematoma in the right frontal lobe on CTA head. Hospital course included tracheostomy with mechanical ventilation. She had panhypopituitarism including CDI. CDI was initially managed by DDAVP 10mcg intranasal nightly and free water flushes. She had central adrenal insufficiency and central hypothyroidism treated by hydrocortisone and levothyroxine respectively. Hospital stay lasted for several months with multiple adjustments to the DDAVP dosage and free water flushes due to fluctuating serum sodium levels. She was started on levetiracetam 750 mg twice daily and oxcarbazepine 300 mg twice daily for seizure like activity. After two months, the oxcarbazepine dose was increased to 450 mg twice daily and later to 600 mg twice daily for breakthrough seizures. DDAVP was then discontinued as she developed hyponatremia. The dose of oxcarbazepine was reduced to 450 mg twice daily and she was subsequently discharged to a facility off DDAVP. Discussion: Postoperative CDI managed by DDAVP was complicated with oxcarbazepine-induced hyponatremia. CDI and sodium levels were controlled with oxcarbazepine after DDAVP discontinuation. Thus, oxcarbazepine has therapeutic potential as an antidiuretic agent as it can stimulate collecting tubule V2 receptor - G protein complex independent of ADH. Presentation: Friday, June 16, 2023

Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?

Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either PKD1 or PKD2 genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, is the only drug that has been proven to attenuate ADPKD progression. Recently, autophagy, a cellular recycling system that facilitates the breakdown and reuse of aged or damaged cellular components, has emerged as a potential contributor to the pathogenesis of ADPKD. However, the precise role of autophagy in ADPKD remains a subject of investigation, displaying a potentially twofold impact. On the one hand, impaired autophagy may promote cyst formation by inducing apoptosis, while on the other hand, excessive autophagy may lead to fibrosis through epithelial to mesenchymal transition. Promising results of autophagy inducers have been observed in preclinical studies. Clinical trials are warranted to thoroughly assess the long-term safety and efficacy of a combination of autophagy inducers with metabolic and/or aquaferetic drugs. This research aims to shed light on the complex involvement of autophagy in ADPKD, explore the regulation of autophagy in disease progression, and highlight the potential of combination therapies as a promising avenue for future investigations.

Terlipressin for the Prevention and Treatment of Renal Decline in Hepatorenal Syndrome: A Drug Profile.

Hepatorenal syndrome stands as one of several potential triggers of acute kidney injury in individuals grappling with either acute or persistent liver ailments. The nature of the decline in kidney function has led to the identification of two variants of hepatorenal syndrome. In cases where terlipressin therapy is accessible, the initial approach involves administering terlipressin alongside albumin. Terlipressin, a synthetic analog of vasopressin, boasts double the preference for vasopressin V1 receptors compared to V2 receptors. The FDA granted approval to terlipressin in September 2022, demonstrating its intrinsic activity, although a significant portion of its function arises from its transformation into lysine vasopressin. This article provides a comprehensive examination of terlipressin's various pharmacodynamic and pharmacokinetic facets, as well as its clinical utility, aiming to keep the scientific community well informed about its safe and efficient utilization.

Efficacy and safety of postoperative preemptive use of tolvaptan for patients with cirrhosis undergoing hepatectomy for hepatocellular carcinoma.

Optimal choice of diuretics in perioperative management remains unclear in enhanced recovery after liver surgery. This study investigated the efficacy and safety of tolvaptan (oral vasopressin V2-receptor antagonist) in postoperative management of patients with liver injury and hepatocellular carcinoma. The patients clinically diagnosed with liver cirrhosis were included in this study. Clinical outcomes of 51 prospective cohort managed with a modified postoperative protocol using tolvaptan (validation group) were compared with 83 patients treated with a conventional management protocol (control group). Postoperative urine output were significantly larger and excessive body weight increase were reduced with no impairment in renal function or serum sodium levels in the validation group. Although the total amount of discharge and trend of serum albumin level were not significantly different among the groups, global incidence of postoperative morbidity was less frequent (19.6% vs. 44.6%, P=0.005) and postoperative stay was significantly shorter (8 days vs.10 days, P=0.008) in the validation group compared with the control group. Tolvaptan could be safely used for the patients with injured liver in postoperative management after hepatectomy and potentially advantageous in the era of enhanced recovery after surgery with its strong diuretic effect and better fluid management.

Target immobilization on glass microfiber membranes as a label-free strategy for hit identification.

The discovery of novel chemical entities targeting G protein-coupled receptors (GPCRs) is usually guided by their receptor affinity. However, traditional affinity assay methods and hit identification procedures are usually laborious and expensive. In this work, the type-2 vasopressin receptor (V2R) was chosen as a prototypical GPCR. Membrane fragments from cells highly expressing SNAP-V2R were immobilized on the surface of a glass microfiber (GMF) coated with O6-benzylguanine (BG). This was achieved by transferring the benzyl group of BG to the active site of the SNAP-tag through a nucleophilic substitution reaction. As a result, a biofilm called SNAP-V2R@GMF-BG was produced that showed good specificity and stability. The adsorption ratio for each V2R ligand treated with SNAP-V2R@GMF-BG was determined by HPLC and exhibited a good linear correlation with the Ki value determined by displacement assays. Furthermore, a Ki prediction assay was performed by comparing the data with that generated by a homogeneous time-resolved fluorescence (HTRF) assay. SNAP-V2R@GMF-BG was also used to screen hit compounds from natural products. After SNAP-V2R@GMF-BG was incubated with the total extract, the ligand that binds to V2R could be separated and subjected to LC‒MS analysis for identification. Baicalein was screened from Clerodendranthus spicatus and verified as a potential V2R antagonist. This V2R-immobilized GMF platform can help determine the affinity of V2R-binding hit compounds and screen the compounds efficiently and accurately.

Metabolic effects of vasopressin in pathophysiology of diabetic kidney disease.

The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.

Investigating the Impact of Selective Modulators on the Renin-Angiotensin-Aldosterone System: Unraveling Their Off-Target Perturbations of Transmembrane Ionic Currents.

The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation, electrolyte balance, and overall cardiovascular health. However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na+ channels, was shown to stimulate peak and late components of voltage-gated Na+ current (INa). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late INa directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca2+-activated K+ channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late INa effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late INa along with a slowing of the inactivation time course of the current. However, telmisartan's presence can also suppress the erg-mediated K+ current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K+ current and the M-type K+ current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding.

Cloning and deorphanization of three inotocin (insect oxytocin/vasopressin-like) receptors and their ligand from the tick Ixodes scapularis

Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These insects also have one inotocin G protein-coupled receptor (GPCR), which is the orthologue of the mammalian oxytocin and vasopressin receptors. The tick Ixodes scapularis belongs to the subphylum Chelicerata, an arthropod taxon different from insects, to which also spiders, scorpions, and mites belong. I. scapularis is an ectoparasite and a health risk for humans, because it transfers pathogenic microorganisms to its human host during a blood meal, thereby causing serious neurological diseases, among them Lyme disease and tick-borne encephalitis (TBE). By annotating the genomic sequence of I. scapularis, we previously found one presumed tick inotocin preprohormone gene and, in contrast to insects, three genes coding for presumed inotocin GPCRs. We now find that these GPCR genes cluster on one genomic contig, suggesting that they originated by recent gene duplications. Closely located on the same contig are also four adipokinetic hormone/corazonin-related peptide (ACP) GPCR genes, and one crustacean cardioactive peptide (CCAP) GPCR gene, suggesting evolutionary relationships. These evolutionary relationships are confirmed by phylogenetic tree analyses of their gene products. We also cloned the tick inotocin preprohormone, which has a structural organization closely resembling mammalian oxytocin and vasopressin preprohormones, including the presence of a conserved neurophysin sequence, having seven cystine bridges. This neurophysin sequence has two cystine-knot domains, but in contrast to mammalian neurophysins, the tick neurophysin contains a canonical prohormone convertase cleavage signal and a peptide C-terminal amidation sequence (GKR), suggesting cleavage into two biologically active cystine-knot peptides. This cleavage/amidation sequence occurs in neurophysins from most hard tick species, but not in other chelicerates. Mature tick inotocin is different from insect inotocin and has the sequence CFITNCPPGamide. Finally, we cloned and stably expressed the three tick inotocin receptors in Chinese Hamster Ovary cells and found that each of them was activated by nanomolar concentrations of tick inotocin (EC50 for ITR1 = 1.6 × 10−8 M; EC50 for ITR2 = 5.8 × 10−9 M; EC50 for ITR3 = 9.3 × 10−9 M), thereby establishing that they are genuine tick inotocin receptors.

Arginine Vasopressin Plays a Role inMicrovascular Dysfunction After ST-Elevation Myocardial Infarction.

Background Coronary microvascular dysfunction (CMD) predicts mortality after ST-elevation-myocardial infarction (STEMI). Arginine vasopressin (AVP) may be implicated, but data in humans are lacking, and no study has investigated the link between arginine vasopressin and invasive measures of CMD. Methods and Results We invasively assessed CMD in 55 patients with STEMI treated with primary percutaneous coronary intervention (PPCI), by measuring the index of microcirculatory resistance after PPCI. In a separate group of 45 patients with STEMI/PPCI, recruited for a clinical trial, we measured infarct size and microvascular obstruction with cardiac magnetic resonance (CMR) imaging at 1 week and 12 weeks post-STEMI. Serum copeptin was measured at 4 time points before and after PPCI in all patients with STEMI. Plasma copeptin levels fell from 92.5 pmol/L before reperfusion to 6.4 pmol/L at 24 hours. Copeptin inversely correlated with diastolic, but not systolic, blood pressure (r=-0.431, P=0.001), suggesting it is released in response to myocardial ischemia. Persistently raised copeptin at 24 hours was correlated with higher index of microcirculatory resistance (r=0.372, P=0.011). Patients with microvascular obstruction on early CMR imaging showed a trend toward higher admission copeptin, which was not statistically significant. Copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Patients with CMD after STEMI have persistently elevated copeptin at 24 hours, suggesting arginine vasopressin may contribute to microvascular dysfunction. Arginine vasopressin receptor antagonists may represent a novel therapeutic option in patients with STEMI and CMD.

Phosphorylation motif dictates GPCR C-terminal domain conformation and arrestin interaction

Arrestin-dependent G protein-coupled receptor (GPCR) signaling pathway is regulated by the phosphorylation state of GPCR's C-terminal domain, but the molecular bases of arrestin:receptor interaction are to be further illuminated. Here we investigated the impact of phosphorylation on the conformational features of the C-terminal region from three rhodopsin-like GPCRs, the vasopressin V2 receptor (V2R), the growth hormone secretagogue or ghrelin receptor type 1a (GHSR), and the β2-adernergic receptor (β2AR). Using phosphomimetic variants, we identified pre-formed secondary structure elements, or short linear motifs (SLiMs), that undergo specific conformational transitions upon phosphorylation. Of importance, such conformational transitions appear to favor arrestin-2 binding. Hence, our results suggest a model in which the phosphorylation-dependent structuration of the GPCR C-terminal regions would modulate arrestin binding and therefore signaling outcomes in arrestin-dependent pathways.

A Brain Region-Dependent Alteration in the Expression of Vasopressin, Corticotropin-Releasing Factor, and Their Receptors Might Be in the Background of Kisspeptin-13-Induced Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Rats.

Previously, we reported that intracerebroventricularly administered kisspeptin-13 (KP-13) induces anxiety-like behavior and activates the hypothalamic-pituitary-adrenal (HPA) axis in rats. In the present study, we aimed to shed light on the mediation of KP-13's stress-evoking actions. The relative gene expressions of the corticotropin-releasing factor (Crf, Crfr1, and Crfr2) and arginine vasopressin (Avp, Avpr1a, and Avpr1b) systems were measured in the amygdala and hippocampus of male Wistar rats after icv KP-13 treatment. CRF and AVP protein content were also determined. A different set of animals received CRF or V1 receptor antagonist pretreatment before the KP-13 challenge, after which either an open-field test or plasma corticosterone levels measurement was performed. In the amygdala, KP-13 induced an upregulation of Avp and Avpr1b expression, and a downregulation of Crf. In the hippocampus, the mRNA level of Crf increased and the level of Avpr1a decreased. A significant rise in AVP protein content was also detected in the amygdala. KP-13 also evoked anxiety-like behavior in the open field test, which the V1 receptor blocker antagonized. Both CRF and V1 receptor blockers reduced the KP-13-evoked rise in the plasma corticosterone level. This suggests that KP-13 alters the AVP and CRF signaling and that might be responsible for its effect on the HPA axis and anxiety-like behavior.

Effect of Neurohypophyseal Hormones on Excretion of Proteins by the Kidneys

Vasopressin (VP) is one of the main factors affecting intraglomerular hemodynamics, filtration pressure and the state of mesangial cells and contributing to the progression of proteinuria. The aim of this work was to study the effect of neurohypophyseal hormones (VP and oxytocin) on urinary protein excretion. Experiments were performed on Wistar rats, healthy and with microalbuminuria caused by minimal damage to the glomerular filter. Microalbuminuria was modeled by administration of D-nitroarginine methyl ester (D-NAME, 50 mg/kg, intraperitoneally). VP (0.05 and 1.5 nmol/kg) and oxytocin (0.15 nmol/kg) were administered to rats intramuscularly, V2-antagonist (15 nmol/kg) and V1a-antagonist (20 nmol/kg) intraperitoneally. To reduce the level of endogenous VP, animals were given water to drink (10 ml/kg), urine was collected for 2 h, and the levels of total protein, albumin, β2-microglobulin, and immunoglobulin G (IgG) were analyzed. In healthy rats, VP at a dose of 0.05 nmol/kg and oxytocin did not affect albumin excretion, but VP at a dose of 1.5 nmol/kg provoked microalbuminuria. In a model of impaired properties of the glomerular filter caused by the D-NAME administration, VP at a dose of 0.05 nmol/kg and oxytocin led to the normalization of albumin excretion, and VP at a dose of 1.5 nmol/kg caused pronounced proteinuria, albumin excretion increased by 100 times, IgG – by 10 times. Blockade of V2 receptors aggravated protein loss caused by D-NAME and VP (1.5 nmol/kg), while blockade of V1a receptors prevented it. Thus, at high concentrations in the blood, VP enhances protein filtration in the kidney. This effect is mediated by V1a receptors and, depending on the barrier properties of the glomerular filter, leads to the development of microalbuminuria or severe proteinuria. Oxytocin and VP at a dose at which it predominantly activates V2 receptors have an antiproteinuric effect. The revealed effects of neurohypophyseal hormones on albumin excretion open up new promising therapeutic targets for the correction of glomerular dysfunctions.

Total and Extracellular Vesicle cAMP Contents in Urine Are Associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) Progression.

ADPKD is the most common genetic renal disease, characterized by the presence of multiple cysts which, through slow and gradual growth, lead to glomerular filtration rate (GFR) decline and end-stage renal disease. Cystic growth is associated with increased intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP). Extracellular vesicles (EVs) are proposed to participate in "remote sensing" by transporting different cargoes, but their relevance to ADPKD progression is poorly understood. This study aimed to determine whether cAMP is contained in urinary EVs and, if so, how total and/or EV cAMP contents participate in disease progression. Fourteen ADPKD patients, naïve for V2 receptor antagonism treatment, and seven controls were studied. Progression was evaluated by estimating GFR (eGFR) and height-adjusted total kidney volume (htTKV). Fresh morning urine was collected to determine cAMP by the competitive radioligand assay. Urine EVs were isolated using an adapted centrifugation method and characterized by electron microscopy, dynamic light scanning, flow cytometry with FITC CD63 labeling, protein and RNA content, and AQP2 and GAPDH mRNA detection. Total and EV cAMP was measurable in both control and patient urine samples. Total cAMP was significantly correlated with eGFR and its annual change but inversely correlated with htTKV. The cAMP-EVs showed a bimodal pattern with htTKV, increasing to ~1 L/m and falling at larger sizes. Our results demonstrate that urine cAMP correlates with ADPKD progression markers, and that its extracellular delivery by EVs could reflect the architectural disturbances of the organ.

The Efficacy, the Treatment Response and the Aquaretic Effects of a Three-Year Tolvaptan Regimen in Polycystic Kidney Disease Patients.

Tolvaptan, a selective vasopressin V2 receptor antagonist, is the first and only approved specific treatment for Autosomal-Dominant Polycystic Kidney Disease (ADPKD), and is used in current clinical practice. Real clinical data are missing. In this retrospective study, 41 ADPKD patients received tolvaptan for 3 years, from 2018 to 2021. Total kidney volume (TKV) was measured using Magnetic Resonance Imaging, at initiation and at the end of the treatment period. A complete biochemistry/hematology profile and a 24 h urine volume collection were performed monthly for the first 18 months and every 3 months thereafter. At the end of the treatment period, the median (IQR) estimated Glomerular Filtration Rate (e-GFR) was 5.3 (-1.3, 8.7) mL/min higher than the expected e-GFR decline without treatment, while the prediction for End Stage Chronic Kidney Disease (ESKD) had been prolonged by 1 (0, 2) year. Total Kidney Volume did not change significantly (2250 (1357) mL at 3 years of treatment vs. 2180 (1091) mL expected without treatment, p = 0.48). Younger patients with a relatively preserved e-GFR, lower hypertension burden, better familiar renal prognosis and more severe imaging data showed better outcomes. The aquaretic adverse effects of tolvaptan did not affect renal function and electrolyte balance in 51 patients, in a follow-up period of 18 months. Consequently, tolvaptan seems to be effective in preventing progression of ADPKD when administered in a timely manner in patients with better familiar renal history, shorter hypertension duration and worse imaging profile. Increased diuresis does not affect treatment efficacy.

Safety and Efficacy of Vaptans in the Treatment of Hyponatremia from Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): A Systematic Review and Meta-Analysis.

The utilization of vasopressin receptor antagonists, known as vaptans, in the management of hyponatremia among patients afflicted with the syndrome of inappropriate antidiuretic hormone (SIADH) remains a contentious subject. This meta-analysis aimed to evaluate the safety and efficacy of vaptans for treating chronic hyponatremia in adult SIADH patients. Clinical trials and observational studies were identified by a systematic search using MEDLINE, EMBASE, and Cochrane Database from inception through September 2022. The inclusion criteria were the studies that reported vaptans' safety or efficacy outcomes compared to placebo or standard therapies. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD 42022357307). Five studies were identified, comprising three RCTs and two cohort studies, enrolling a total of 1840 participants. Regarding short-term efficacy on days 4-5, vaptans exhibited a significant increase in serum sodium concentration from the baseline in comparison to the control group, with a weighted mean difference of 4.77 mmol/L (95% CI, 3.57, 5.96; I2 = 34%). In terms of safety outcomes, the pooled incidence rates of overcorrection were 13.1% (95% CI 4.3, 33.6; I2 = 92%) in the vaptans group and 3.3% (95% CI 1.6, 6.6; I2 = 27%) in the control group. Despite the higher correction rate linked to vaptans, with an OR of 5.72 (95% CI 3.38, 9.70; I2 = 0%), no cases of osmotic demyelination syndrome were observed. Our meta-analysis comprehensively summarizes the efficacy and effect size of vaptans in managing SIADH. While vaptans effectively raise the serum sodium concentration compared to placebo/fluid restriction, clinicians should exercise caution regarding the potential for overcorrection.

Surprising Behavior Changes in Genetically Modified Syrian Hamsters

Social behavior and communication are key to building relationships in most species. Vasopressin, a neurochemical commonly known for regulating blood pressure and water balance, also plays a critical role in regulating social behavior and communication. Here, we show that deleting vasopressin receptors can lead to behavioral changes that are opposite of what is expected.