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Scientific Reports Apr 2024Arginine-vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine...
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.
Topics: Humans; Arginine Vasopressin; HEK293 Cells; Cyclic AMP; Receptors, Vasopressin; Biosensing Techniques; Deamino Arginine Vasopressin; Animals; Biological Assay
PubMed: 38658606
DOI: 10.1038/s41598-024-60035-4 -
International Journal of Molecular... Jun 2024The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is...
The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is present in fish. Limited information suggested that vasopressin and its homologs may also influence reproductive function. In the present study, we investigated the direct effect of AVT on spermatogenesis, using zebrafish as a model organism. Results demonstrate that AVT and its receptors (, , , and ) are expressed in the zebrafish brain and testes. The direct action of AVT on spermatogenesis was investigated using an ex vivo culture of mature zebrafish testes for 7 days. Using histological, morphometric, and biochemical approaches, we observed direct actions of AVT on zebrafish testicular function. AVT treatment directly increased the number of spermatozoa in an androgen-dependent manner, while reducing mitotic cells and the proliferation activity of type B spermatogonia. The observed stimulatory action of AVT on spermiogenesis was blocked by flutamide, an androgen receptor antagonist. The present results support the novel hypothesis that AVT stimulates short-term androgen-dependent spermiogenesis. However, its prolonged presence may lead to diminished spermatogenesis by reducing the proliferation of spermatogonia B, resulting in a diminished turnover of spermatogonia, spermatids, and spermatozoa. The overall findings offer an insight into the physiological significance of vasopressin and its homologs in vertebrates as a contributing factor in the multifactorial regulation of male reproduction.
Topics: Animals; Zebrafish; Male; Spermatogenesis; Vasotocin; Testis; Receptors, Vasopressin; Zebrafish Proteins; Spermatozoa; Cell Proliferation; Spermatogonia
PubMed: 38928267
DOI: 10.3390/ijms25126564 -
BioRxiv : the Preprint Server For... Nov 2023Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial...
Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial hypothalamus (VMH) that represents an internal state of aggressiveness. Line attractors can be implemented by recurrent connectivity and/or neuromodulatory signaling, but evidence for the latter is scant. Here we show that neuropeptidergic signaling is necessary for line attractor dynamics in this system, using a novel approach that integrates cell type-specific, anatomically restricted CRISPR/Cas9-based gene editing with microendoscopic calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1 neurons that control aggression suppressed attack, reduced persistent neural activity and eliminated line attractor dynamics, while only modestly impacting neural activity and sex- or behavior-tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.
PubMed: 37961374
DOI: 10.1101/2023.11.01.565073 -
Cureus Sep 2023Vasodilatory shock can be caused by septic shock, neurogenic shock, anaphylaxis, drugs, and toxins. Vasopressin is commonly used for the restoration of vasomotor tone in...
Vasodilatory shock can be caused by septic shock, neurogenic shock, anaphylaxis, drugs, and toxins. Vasopressin is commonly used for the restoration of vasomotor tone in vasodilatory shock due to sepsis. This agent exerts its vasoconstrictive effect via smooth muscle V1 receptors and has antidiuretic activity via kidney V2 receptors. Stimulation of V2 receptors results in the integration of aquaporin 2 channels into the apical membrane of collecting ducts leading to free water reabsorption. This antidiuretic action of vasopressin predisposes to hyponatremia. Yet, the development of hyponatremia with the use of vasopressin in critically ill patients with sepsis is rare. A 75-year-old female presented after a suicidal attempt by ingestion of amlodipine and lisinopril. Despite adequate intravenous fluids administration, she remained hypotensive, requiring the initiation of vasopressors. She developed hyponatremia after initiation of vasopressin due to the absence of endotoxemia, and her serum sodium normalized once vasopressin was discontinued. We recommend monitoring for hyponatremia as a complication of vasopressin, especially in patients without sepsis.
PubMed: 37829951
DOI: 10.7759/cureus.45053 -
Molecular Genetics & Genomic Medicine Apr 2024Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling...
INTRODUCTION
Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body's water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X-linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney.
METHODS
Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon-intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines.
RESULTS
In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study.
DISCUSSION
As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype-phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation.
Topics: Humans; Diabetes Insipidus, Nephrogenic; Aquaporin 2; Iran; Mutation; Water; Diabetes Mellitus
PubMed: 38622833
DOI: 10.1002/mgg3.2421 -
Trials Feb 2024Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor...
HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial.
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD.
METHODS
The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care.
OUTCOMES
The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume.
CONCLUSION
The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.
Topics: Humans; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Hydrochlorothiazide; Quality of Life; Glomerular Filtration Rate; Antidiuretic Hormone Receptor Antagonists; Kidney; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 38355627
DOI: 10.1186/s13063-024-07952-x -
Gastroenterology Insights Dec 2023Hepatorenal syndrome stands as one of several potential triggers of acute kidney injury in individuals grappling with either acute or persistent liver ailments. The...
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.
PubMed: 37873544
DOI: 10.3390/gastroent14040031 -
PloS One 2024Arginine vasopressin (AVP) and oxytocin (OT) are well-known as neuropeptides that regulate various social behaviors in mammals. However, little is known about their role...
Arginine vasopressin (AVP) and oxytocin (OT) are well-known as neuropeptides that regulate various social behaviors in mammals. However, little is known about their role in mouse female sexual behavior. Thus, we investigated the role of AVP (v1a and v1b) and OT receptors on female sexual behavior. First, we devised a new apparatus, the bilevel chamber, to accurately observe female mouse sexual behavior. This apparatus allowed for a more precisely measurement of lordosis as receptivity and rejection-like behavior (newly defined in this study), a reversed expression of proceptivity. To address our research question, we evaluated female sexual behavior in mice lacking v1a (aKO), v1b (bKO), both v1a and v1b (dKO), and OT (OTRKO) receptors. aKO females showed decreased rejection-like behavior but a normal level of lordosis, whereas bKO females showed almost no lordosis and no change in rejection-like behavior. In addition, dKO females showed normal lordosis levels, suggesting that the v1b receptor promotes lordosis, but not necessarily, while the v1a receptor latently suppresses it. In contrast, although OTRKO did not influence lordosis, it significantly increased rejection-like behavior. In summary, the present results demonstrated that the v1a receptor inhibits proceptivity and receptivity, whereas the v1b and OT receptors facilitate receptivity and proceptivity, respectively.
Topics: Animals; Female; Receptors, Vasopressin; Receptors, Oxytocin; Sexual Behavior, Animal; Mice; Mice, Knockout; Male; Oxytocin; Mice, Inbred C57BL; Arginine Vasopressin
PubMed: 38900750
DOI: 10.1371/journal.pone.0304703 -
Brain Research Bulletin Oct 2023Oxytocin (OXT) is secreted in a large amount during the middle and late pregnancy. Except for the regulation of functions related to childbirth, OXT is involved in the...
Oxytocin (OXT) is secreted in a large amount during the middle and late pregnancy. Except for the regulation of functions related to childbirth, OXT is involved in the regulation of cognition, social behavior, addiction, pain and so on. Our aim is to confirm the increase of OXT content in mice in late pregnancy is the main cause of itch during pregnancy and observe whether exogenously administered OXT can induce or increase itch sensitivity. The research shows that itch sensitivity of mice increased significantly in late pregnancy and basically returned to normal one day after delivery. The number of OXT-positive neurons in paraventricular nucleus (PVN) and the content of OXT in serum of the late pregnant mice increased significantly, and decreased sharply after delivery. Intradermal injection of low concentration of OXT (0.2 nmol/L) could not induce scratching behavior in mice, but high concentration of OXT (5 nmol/L, 10 nmol/L) could do this in a dose-dependent manner. Low concentration of OXT significantly increased the itch sensitivity to histamine. Intradermal injection of oxytocin receptor (OXTR) or arginine vasopressin-1a receptor (AVPR1A) antagonist did not affect histamine-induced scratching behavior, but both reversed the increase of itch sensitivity in late pregnant mice or the facilitated itch sensitivity by OXT. Study suggests that both endogenous and exogenous increases in OXT can increase the body's sensitivity to itch, and even induce itch directly. Pruritus during pregnancy is closely related to the increase of OXT content in vivo. In the periphery, the itch-promoting effect of OXT is mediated by OXTR and AVPR1A.
Topics: Female; Mice; Animals; Pregnancy; Oxytocin; Histamine; Receptors, Oxytocin; Receptors, Vasopressin; Pruritus
PubMed: 37633617
DOI: 10.1016/j.brainresbull.2023.110749 -
The Journal of Spinal Cord Medicine Nov 2023Activity-based recovery training (ABRT) reverses spinal cord injury (SCI) induced polyuria and alterations of biomarkers involved with fluid balance, including...
Activity-based recovery training (ABRT) reverses spinal cord injury (SCI) induced polyuria and alterations of biomarkers involved with fluid balance, including expression levels of kidney vasopressin 2 receptors. However, void volumes do not return to pre-injury baseline levels, indicating a combinatorial approach may be necessary. In the current study, acute effects of a pharmacological intervention versus placebo were examined in male rats that had received 70 daily ABRT sessions. The treatment, desmopressin (DDAVP - synthetic analogue of arginine vasopressin), an antidiuretic therapy used for the management of bedwetting in children and central diabetes insipidus, has previously shown some promise in a few limited cohorts of SCI individuals having nocturnal polyuria. A total of 70 sessions of ABRT over a 10-week timeframe again reduced the overproduction of urine, but not completely to pre-SCI baseline levels. DDAVP treatment maintained but did not further reduce the level of urine output in the ABRT group without continuous exercise, demonstrating either intervention/treatment alone is effective, despite no additive effect. Although intake did not change from pre-injury levels despite polyuria, DDAVP treatment also reduced drink volume. Further studies are needed as the mechanisms underlying changes in fluid and solute balance are likely multi-factorial involving a complex interaction between the neural (both central and peripheral) control of systems mediating thirst, urinary output, and cardiovascular regulation.
Topics: Humans; Child; Male; Rats; Animals; Deamino Arginine Vasopressin; Polyuria; Rats, Wistar; Spinal Cord Injuries; Urination
PubMed: 35604340
DOI: 10.1080/10790268.2022.2069538