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BackgroundAlthough tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response.MethodsThe study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver-operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals.ResultsA cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961; sensitivity, 89.8%; specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated.ConclusionsThe cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week; this value is expected to be an effective indicator of response to tolvaptan in clinical practice.

Background The phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) clinical trial demonstrated the beneficial effect of tolvaptan on kidney growth and function in subjects aged 18–50 years over a 3-year period. However, it did not specifically assess the use of tolvaptan in adolescents and young adults (AYAs) with ADPKD. Methods A post hoc analysis of the TEMPO 3:4 trials was performed for patients aged 18–24 years. The primary outcome was the annual rate of change in total kidney volume (TKV). The secondary outcome was to evaluate long-term safety of tolvaptan using Hy’s law of hepatotoxicity. Results A total of 51 patients in the 18–24 age group were analyzed (tolvaptan: 29, placebo: 22). The tolvaptan group had a lower mean percentage of TKV growth per year compared to the placebo group (3.9% vs. 6.5%, P  = 0.0491). For secondary outcomes, 63 patients in the AYA subgroup were evaluated. In both the AYA and adult groups, none of the patients met the criteria for Hy’s law of hepatotoxicity. Conclusions This post hoc analysis suggests that tolvaptan, with appropriate patient selection and management, can provide effective and acceptably safe treatment in AYAs with ADPKD. Impact Tolvaptan slows the increase in total kidney volume in patients aged 18–24 years with ADPKD. Tolvaptan posed no risk of potential liver injury measured via Hy’s law of hepatotoxicity in the AYA stratum. This study suggests that tolvaptan has beneficial outcomes in AYAs. This post hoc analysis suggests the need for additional studies with a larger pediatric patient population. The impact is significant as tolvaptan had not been specifically examined in the AYA patient population previously.

Plant-derived nanovesicles (PDNVs) are promising candidates for next-generation drug delivery system due to their scalability, low cytotoxicity and immunogenicity, and efficient cellular uptake. Here, tomato fruit-derived PDNVs were loaded with tolvaptan, a vasopressin V2-receptor antagonist with the aim to reduce drug cytotoxicity, control drug release and to improve drug efficiency in vitro. Tolvaptan was encapsulated by extrusion and electroporation. Entrapment efficiency (EE%) and drug loading capacity (DLC%) were optimized by changing the drug-to-PDNV ratio and time-dependent drug release rate was evaluated at two different pH. Tolvaptan-loaded PDNVs were characterized using physiochemical and morphological methods. Cellular uptake of fluorescently labelled tolvaptan-loaded PDNVs was evaluated. The cytotoxicity and effects of tolvaptan-loaded PDNVs on cyst formation and cell migration were studied in different renal cell cultures. Electroporation resulted in higher EE% and DLC% than extrusion for the encapsulation of tolvaptan into PDNVs. MDCK cells efficiently uptake tolvaptan-loaded PDNVs. The release of the tolvaptan was time and pH dependent. Enhanced cell proliferation, suppressed cyst growth, and altered cyst morphology compared with controls was observed. Migration assay demonstrated that tolvaptan-encapsulated PDNVs had a favourable effect on enhancing wound healing and cell migration in renal cells. Tolvaptan-loaded PDNVs show promising features as a natural next-generation nanoscale delivery system in vitro for time and pH-dependent release of hydrophobic drugs, such as tolvaptan.

The vasopressin V2 receptor (V2R), a class A G protein-coupled receptor, is essential for regulating body water homeostasis. V2R antagonists have emerged as promising treatments for hyponatremia; however, the absence of structural information for antagonist-bound V2R hampers our understanding of antagonist recognition and the targeted design of V2R antagonists. In this study, we present two cryo-electron microscopy structures of inactive V2R bound to the clinically approved antagonists tolvaptan and conivaptan. Combined with functional analyses and molecular dynamic simulations, these structures reveal distinct binding poses: tolvaptan is deeply inserted within the binding pocket, whereas conivaptan is positioned at a shallower depth. Integrated analyses further define critical pharmacophoric features governing antagonist activity and unveil a TM7 helical conformation-dependent antagonism mechanism that is distinct from classical GPCR inactivation modes. Our findings deepen understanding of antagonist recognition and antagonism of V2R, providing a foundation for the development of V2R-targeted therapies. The vasopressin V2 receptor (V2R) is a key regulator of water balance, and its antagonists are promising therapeutics for hyponatremia. Here, the authors offer structural insights into antagonist recognition and antagonism of V2R.

Inhibitors of the arginine-vasopressin (AVP) V2 receptor (V2R) are key therapeutic compounds for treating hyponatremia or polycystic kidney diseases. Rational drug design based on experimental G protein-coupled receptor structures is a powerful avenue to develop better drugs. So far, the lack of inhibitor-bound V2R structures has impaired this strategy. Here we describe the cryo-electron microscopy structures of the V2R in complex with two selective inverse agonists, the non-peptide Tolvaptan (TVP) and the green mamba snake Mambaquaretin toxin (MQ1). Both ligands bind into the orthosteric binding site but with substantial differences. TVP binds deeper than MQ1, and directly contacts the toggle switch residue W2846.48 in the transmembrane domain 6. The Kunitz-fold toxin displays extensive contacts with extracellular and transmembrane residues. As anticipated from TVP and MQ1 pharmacological properties, both structures represent inactive V2R conformations. Their comparison with those of the active AVP-bound V2R reveals the molecular mechanisms modulating receptor activity. The mini-protein MQ1-bound V2R structure suggests a new pharmacology approach for treating water homeostasis and renal diseases.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (−8.77–20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis—a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies.

Inflammation plays a crucial role in the progression of autosomal dominant polycystic kidney disease (ADPKD). While tolvaptan is primarily known for its vasopressin V2 receptor antagonism, its potential anti-inflammatory effects remain under investigation. This study aimed to evaluate the impact of tolvaptan on inflammatory markers and renal progression in ADPKD patients. This retrospective, two-center cohort study included 80 ADPKD patients, with 40 receiving tolvaptan and 40 serving as controls. Inflammatory markers, including C-reactive protein (CRP), systemic inflammatory index (SII), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and renal function parameters such as glomerular filtration rate (GFR) and proteinuria, were analyzed over a 1-year follow-up period. In the tolvaptan group, CRP, SII, PLR, proteinuria, and uric acid levels significantly decreased, whereas these markers increased in the control group. GFR remained stable in the tolvaptan group but declined significantly in the control group ( p  < 0.001). No significant correlation was found between GFR and inflammatory markers in either group. Our findings suggest that tolvaptan may contribute to reducing systemic inflammation in ADPKD patients while preserving renal function. These results align with previous studies indicating a link between inflammation and ADPKD progression.

Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor—nuclear factor erythroid 2-related factor 2 (Nrf2)—has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.

The vasopressin V receptor (V R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive V R conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvaptan-V R interactions, potentially aiding the design of novel antagonists for V R and other G protein-coupled receptors.