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1.
Peptides ; 173: 171151, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38215943

RESUMO

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disorder in which vasopressin-secreting neurons degenerate over time due to the production of mutant proteins. We have demonstrated therapeutic effects of chemical chaperones in an FNDI mouse model, but the complexity and length of this evaluation were problematic. In this study, we established disease-specific mouse induced pluripotent stem cells (iPSCs) from FNDI-model mice and differentiated vasopressin neurons that produced mutant proteins. Fluorescence immunostaining showed that chemical chaperones appeared to protect vasopressin neurons generated from iPSCs derived from FNDI-model mice. Although KCL stimulation released vasopressin hormone from vasopressin neurons generated from FNDI-derived iPSCs, vasopressin hormone levels did not differ significantly between baseline and chaperone-added culture. Semi-quantification of vasopressin carrier protein and mutant protein volumes in vasopressin neurons confirmed that chaperones exerted a therapeutic effect. This research provides fundamental technology for creating in vitro disease models using human iPSCs and can be applied to therapeutic evaluation of various degenerative diseases that produce abnormal proteins.


Assuntos
Diabetes Insípido Neurogênico , Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Humanos , Camundongos , Animais , Arginina Vasopressina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Vasopressinas/farmacologia , Vasopressinas/metabolismo , Diabetes Insípido Neurogênico/metabolismo , Neurofisinas/genética , Proteínas Mutantes/metabolismo , Mutação
2.
Psychoneuroendocrinology ; 161: 106951, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38194845

RESUMO

Oxytocin is a pleiotropic neuropeptide that plays roles in biological processes ranging from birth, lactation, and social bonding to immune function, cardiovascular repair, and regulation of appetite. Although measurements of endogenous oxytocin concentrations have been performed for more than 50 years, the ability to measure oxytocin accurately poses notable challenges. One potential solution for overcoming these challenges involves measurement of oxytocin's carrier molecule - neurophysin I (NP-1) - as a surrogate biomarker. NP-1 is secreted in equimolar concentrations with oxytocin but has a longer half-life, circulates in higher concentrations, and can be measured using a sandwich immunoassay. We report experiments that 1) analytically validate a commercially available NP-1 sandwich immunoassay for use with human plasma and urine samples, 2) confirm the specificity of this assay, based on detection of NP-1 in plasma from wild-type but not oxytocin knockout mice, 3) demonstrate that NP-1 concentrations are markedly elevated in late pregnancy, consistent with studies showing substantial increases in plasma oxytocin throughout gestation, and 4) establish strong correlation between NP-1 and plasma oxytocin concentrations when oxytocin is measured in extracted (but not non-extracted) plasma. The NP-1 assay used in this study has strong analytical properties, does not require time-intensive extraction protocols, and the assay itself can be completed in < 2 h (compared to 16-24 h for a competitive oxytocin immunoassay). Our findings suggest that much like copeptin has become a useful surrogate biomarker in studies of vasopressin, measurements of NP-1 have similar potential to advance oxytocin research.


Assuntos
Neurofisinas , Ocitocina , Camundongos , Animais , Feminino , Gravidez , Humanos , Ocitocina/metabolismo , Neurofisinas/metabolismo , Lactação , Imunoensaio , Bioensaio
3.
Mol Med Rep ; 25(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34796908

RESUMO

Prenatal food restriction (PFR) induces dysfunction of the hypothalamic­pituitary­adrenal (HPA) axis in the adult offspring. The aim of the present study was to identify the underlying mechanism of this process. Pregnant rats were placed on a restricted diet between gestational day 11 and 21. The offspring were fed with a high­fat diet and were subjected to unpredictable chronic stress (UCS) from postnatal week 17 to 20. A higher serum corticosterone (CORT) level was observed in the PFR fetuses. Although lower arginine vasopressin (AVP), hippocampal vesicular glutamate transporter 2 (vGLUT2) and glutamic acid decarboxylase 65 (GAD65) mRNA expression levels were detected in the hippocampi of PFR fetuses, the ratio of the mRNA expression levels of vGLUT2 and GAD65 was higher compared with that of the controls, which was accompanied by histopathological and ultrastructural abnormalities of both the hypothalamus and hippocampus. However, there were no marked changes in the hippocampal expression levels of glucocorticoids receptor (GR) and mineralocorticoids receptor (MR) or the ratio of MR/GR ratio. After the fetuses had matured, lower serum CORT and adrenocorticotropic hormone (ACTH) levels were observed in PFR rats without UCS when compared with the control. A higher rise rate of serum ACTH was also observed after UCS when compared with that in rats without UCS. Furthermore, the hypothalamic mRNA expression level of corticotrophin­releasing hormone (CRH) was lower in PFR rats without UCS, while expression levels of CRH, AVP, GAD65 and vGLUT2 were enhanced after UCS when compared with the control, accompanied by an increased vGLUT2/GAD65 expression ratio. MR mRNA expression was lower, and GR mRNA expression was higher in the hippocampus of the PFR rats without UCS when compared with the control. However, the mRNA expression levels of both MR and GR in the PFR rats were higher compared with those of the control after UCS, which was accompanied histopathological changes in the dentate gyrus, cornu ammonis (CA1) and CA3 areas. In summary, it was suggested that PFR induced fetal alterations of the HPA axis manifesting as hypothalamic hyperexcitability and poor hippocampal feedback, which persisted to adulthood and affected the behavior of the rat offspring.


Assuntos
Desenvolvimento Fetal , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Corticosterona , Hormônio Liberador da Corticotropina/metabolismo , Dieta Hiperlipídica , Feminino , Masculino , Neurofisinas , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Precursores de Proteínas , Ratos , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Vasopressinas
4.
Clin Neuropathol ; 41(1): 18-24, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34142952

RESUMO

INTRODUCTION: Hypothalamic hamartoma (HH) is a rare developmental disorder presenting with gelastic seizures or precocious puberty attributed to gonadotrophin-releasing hormone expression by the hamartoma. The histogenesis of HH is uncertain, and diagnosis of HH is difficult in small biopsies due to its close resemblance to normal hypothalamic nuclei. TTF-1 and arginine vasopressin (AVP) are associated with gonadotropin-releasing hormone release. MATERIALS AND METHODS: In this study, we explored the expression pattern of TTF-1 and AVP in HH and its utility, if any, in diagnosis. We reviewed the clinical, radiologic, and histopathological features of 23 HH diagnosed over the past decade at our Institute. RESULTS: The age at presentation ranged from 11 months to 34 years with gelastic seizures (82.6%), precocious puberty (17.4%), and developmental delay (8.7%) as presenting symptoms. On imaging, all the lesions (n = 9) involved the posterior and tuberal group of hypothalamic nuclei, while 5 cases involved the anterior hypothalamus. Anatomically, the lesions involved mammillary body, arcuate and periventricular nuclei. On histopathology, 52% cases revealed nodular arrangement of small neurocytic cells separated by glial stroma. TTF-1 and AVP immunoreactivity was absent in all the cases, whereas in normal hypothalamus, AVP was expressed in periventricular nuclei. CONCLUSION: Our results suggest that immunoexpression of TTF-1 is absent in HH, particularly in those arising from the posterior hypothalamus, and this can be used in small biopsies to distinguish from a normal hypothalamus as well as from posterior pituitary tumors.


Assuntos
Proteínas de Ligação a DNA , Hamartoma , Doenças Hipotalâmicas , Neurofisinas , Precursores de Proteínas , Puberdade Precoce , Fatores de Transcrição , Vasopressinas , Arginina Vasopressina , Proteínas de Ligação a DNA/imunologia , Hamartoma/diagnóstico , Humanos , Doenças Hipotalâmicas/diagnóstico , Lactente , Neurofisinas/imunologia , Precursores de Proteínas/imunologia , Fatores de Transcrição/imunologia , Vasopressinas/imunologia
5.
Endocr J ; 69(1): 95-100, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-34544934

RESUMO

The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.


Assuntos
Diabetes Insípido Neurogênico , Diabetes Mellitus , Enurese Noturna , Adulto , Arginina Vasopressina , Criança , Diabetes Insípido Neurogênico/diagnóstico , Diabetes Insípido Neurogênico/genética , Feminino , Humanos , Masculino , Mutação , Neurofisinas/genética , Enurese Noturna/etiologia , Enurese Noturna/genética , Linhagem
6.
Dalton Trans ; 50(47): 17487-17490, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34796892

RESUMO

The reactions of the medicinal gold(I) compound auranofin and its close analogues with vasopressin and the diselenide analogue were comparatively investigated by LC-electrospray MS/MS. Evidence is gained of the possible cleavage of the S-S and Se-Se bridges induced by Au(I). Notably, we found that, in the absence of reducing agents, the sulfur and selenium atoms are metallated only at high temperature (70 °C) with the preferential binding of gold to selenium. The reaction with the S-S bridge can take place at physiological temperature (37 °C) under reducing conditions. The implications of these results are discussed in the general frame of the reactivity of biologically relevant soft Lewis acids with peptides and proteins.


Assuntos
Neurofisinas/antagonistas & inibidores , Compostos Organoáuricos/farmacologia , Compostos Organosselênicos/farmacologia , Precursores de Proteínas/antagonistas & inibidores , Vasopressinas/antagonistas & inibidores , Humanos , Neurofisinas/metabolismo , Compostos Organoáuricos/química , Compostos Organosselênicos/química , Precursores de Proteínas/metabolismo , Vasopressinas/metabolismo
7.
Int J Mol Sci ; 22(21)2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34768894

RESUMO

The neurons secreting oxytocin (OXY) and vasopressin (AVP) are located mainly in the supraoptic, paraventricular, and suprachiasmatic nucleus of the brain. Oxytocinergic and vasopressinergic projections reach several regions of the brain and the spinal cord. Both peptides are released from axons, soma, and dendrites and modulate the excitability of other neuroregulatory pathways. The synthesis and action of OXY and AVP in the peripheral organs (eye, heart, gastrointestinal system) is being investigated. The secretion of OXY and AVP is influenced by changes in body fluid osmolality, blood volume, blood pressure, hypoxia, and stress. Vasopressin interacts with three subtypes of receptors: V1aR, V1bR, and V2R whereas oxytocin activates its own OXTR and V1aR receptors. AVP and OXY receptors are present in several regions of the brain (cortex, hypothalamus, pons, medulla, and cerebellum) and in the peripheral organs (heart, lungs, carotid bodies, kidneys, adrenal glands, pancreas, gastrointestinal tract, ovaries, uterus, thymus). Hypertension, myocardial infarction, and coexisting factors, such as pain and stress, have a significant impact on the secretion of oxytocin and vasopressin and on the expression of their receptors. The inappropriate regulation of oxytocin and vasopressin secretion during ischemia, hypoxia/hypercapnia, inflammation, pain, and stress may play a significant role in the pathogenesis of cardiovascular diseases.


Assuntos
Anormalidades Cardiovasculares , Ocitocina/metabolismo , Vasopressinas/metabolismo , Axônios/metabolismo , Encéfalo/metabolismo , Anormalidades Cardiovasculares/etiologia , Anormalidades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Humanos , Hipertensão/etiologia , Hipertensão/metabolismo , Pulmão/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Neurônios/metabolismo , Neurofisinas/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Ocitocina/metabolismo
8.
Presse Med ; 50(4): 104093, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34718110

RESUMO

Diabetes insipidus (DI) is a disorder characterized by a high hypotonic urinary output of more than 50ml per kg body weight per 24 hours, with associated polydipsia of more than 3 liters a day [1,2]. Central DI results from inadequate secretion and usually deficient synthesis of Arginine vasopressin (AVP) in the hypothalamus or pituitary gland. Besides central DI further underlying etiologies of DI can be due to other primary forms (renal origin) or secondary forms of polyuria (resulting from primary polydipsia). All these forms belong to the Polyuria Polydipsia Syndrom (PPS). In most cases central and nephrogenic DI are acquired, but there are also congenital forms caused by genetic mutations of the AVP gene (central DI) [3] or by mutations in the gene for the AVP V2R or the AQP2 water channel (nephrogenic DI) [4]. Primary polydipsia (PP) as secondary form of polyuria includes an excessive intake of large amounts of fluid leading to polyuria in the presence of intact AVP secretion and appropriate antidiuretic renal response. Differentiation between the three mentioned entities is difficult [5], especially in patients with Primary polydipsia or partial, mild forms of DI [1,6], but different tests for differential diagnosis, most recently based on measurement of copeptin, and a thorough medical history mostly lead to the correct diagnosis. This is important since treatment strategies vary and application of the wrong treatment can be dangerous [7]. Treatment of central DI consists of fluid management and drug therapy with the synthetic AVP analogue Desmopressin (DDAVP), that is used as nasal or oral preparation in most cases. Main side effect can be dilutional hyponatremia [8]. In this review we will focus on central diabetes insipidus and describe the prevalence, the clinical manifestations, the etiology as well as the differential diagnosis and management of central diabetes insipidus in the out- and inpatient setting.


Assuntos
Diabetes Insípido , Polidipsia , Poliúria , Adulto , Antidiuréticos/uso terapêutico , Aquaporina 2/genética , Criança , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido/diagnóstico , Diabetes Insípido/etiologia , Diabetes Insípido/terapia , Diagnóstico Diferencial , Glicopeptídeos/análise , Humanos , Mutação , Neurofisinas/genética , Neurofisinas/metabolismo , Hipófise/diagnóstico por imagem , Hipófise/metabolismo , Polidipsia/classificação , Polidipsia/diagnóstico , Polidipsia/etiologia , Poliúria/diagnóstico , Poliúria/etiologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Vasopressinas/genética , Vasopressinas/metabolismo
9.
Endokrynol Pol ; 72(5): 566-571, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34378786

RESUMO

Arginine vasopressin (AVP), which is also called antidiuretic hormone (ADH), is a neurohormone synthetized from a pre-pro-hormone precursor in the supraoptic and paraventricular nuclei of the hypothalamus in response to increased plasma osmolality and decreased blood volume. AVP exerts several effects by binding to three different receptors: V1aR, V1bR, and V2R. In recent years, it has been suggested that increased plasma concentration of AVP may play a causal role in the development of type 2 diabetes, the metabolic syndrome, renal dysfunction and cardiovascular disease by influencing glucose homeostasis and lipid metabolism through several possible mechanisms involving V1aR and V1bR. V1aR located in the liver is involved in hepatic glycogenolysis and gluconeogenesis. V1bR, found in the pituitary gland and pancreas, mediates secretion of adrenocorticotrophic hormone (ACTH), insulin, and glucagon. However, AVP's clinical use as a biomarker is limited due to its short half-life in plasma (16-20 minutes), small size, and poor stability, which make direct measurement difficult. Copeptin, the biologically inactive, stable, C-terminal part of pro-vasopressin, is co-secreted with AVP in equimolar amounts and thus is considered an adequate and clinically useful surrogate marker of AVP. The aim of this review is to assess the current state of knowledge about the potential role of copeptin as a novel biomarker of cardiometabolic syndrome on the basis of recent scientific literature published up to December 2020 and searches of the PubMed, Google Scholar, and Web of Science databases.


Assuntos
Arginina Vasopressina/sangue , Doenças Cardiovasculares/diagnóstico , Glicopeptídeos/fisiologia , Síndrome Metabólica/diagnóstico , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 2 , Glicopeptídeos/sangue , Humanos , Síndrome Metabólica/sangue , Neurofisinas , Valor Preditivo dos Testes , Precursores de Proteínas , Vasopressinas/sangue
10.
Endocrine ; 74(1): 188-192, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34319541

RESUMO

PURPOSE: Familial neurohypophysial diabetes insipidus (FNDI), commonly caused by autosomal dominant arginine vasopressin (AVP) mutations, is a rare condition in which vasopressin fails in regulating body's level of water with final polyuria and polydipsia. Genetic testing in familial cases of FNDI should be carry out to ensure adequate treatments and avoid disease manifestations especially in infants. METHODS: In this study, we investigated three-generations of a large Italian family with clinical diagnosis of familial central diabetes insipidus for the presence of potential pathogenic mutations in the AVP gene. RESULTS: We identified a heterozygous missense mutation (c.154 T > A; p.C52S) in AVP gene in all affected members studied of a large Italian family. In silico tools were used to investigate the pathogenic role of the mutation and three-dimensional protein structure predicted that the p.C52S impairs disulfide bridges formation resulting in misfolding of the protein. CONCLUSIONS: This is the first study that identified a novel missense p.C52S mutation as causative of central diabetes insipidus in a large Italian pedigree.


Assuntos
Diabetes Insípido Neurogênico , Diabetes Insípido , Diabetes Mellitus , Arginina Vasopressina/genética , Diabetes Insípido Neurogênico/genética , Feminino , Humanos , Itália , Masculino , Mutação , Mutação de Sentido Incorreto , Neurofisinas/genética , Linhagem
11.
Endocrine ; 74(3): 658-665, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34232487

RESUMO

PURPOSE: Familial neurohypophyseal diabetes insipidus (FNDI), a rare disorder, which is clinically characterized by polyuria and polydipsia, results from mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. The aim of this study was to perform functional analyses of three different mutations (p.G45C, 207_209delGGC, and p.G88V) defined in the AVP-NPII gene of patients diagnosed with FNDI, which are not included in the literature. METHODS: For functional analysis studies, the relevant mutations were created using PCR-based site-directed mutagenesis and restriction fragment replacement strategy and expressed in Neuro2A cells. AVP secretion into the cell culture medium was determined by radioimmunoassay (RIA) analysis. Fluorescence imaging studies were conducted to determine the differences in the intracellular trafficking of wild-type (WT) and mutant AVP-NPII precursors. Molecular dynamics (MD) simulations were performed to determine the changing of the conformational properties of domains for both WT and 207-209delGGC mutant structures and dynamics behavior of residues. RESULTS: Reduced levels of AVP in the supernatant culture medium of p.G45C and p.G88V transfected cells compared to 207_209delGGC and WT cells were found. Fluorescence imaging studies showed that a substantial portion of the mutant p.G45C and p.G88V AVP-NPII precursors appeared to be located in the endoplasmic reticulum (ER), whereas 207_209delGGC and WT AVP-NPII precursors were distributed throughout the cytoplasm. CONCLUSIONS: The mutations p.G45C and p.G88V cause a failure in the intracellular trafficking of mutant AVP-NPII precursors. However, 207_209delGGC mutation does not result in impaired cellular trafficking, probably due to not having any significant effect in processes such as the proper folding, gain of three-dimensional structure, or processing. These results will provide valuable information for understanding the influence of mutations on the function of the AVP precursor hormone and cellular trafficking. Therefore, this study will contribute to elucidate the mechanisms of the molecular pathology of AVP-NPII mutations.


Assuntos
Diabetes Insípido Neurogênico , Diabetes Insípido , Diabetes Mellitus , Neurofisinas , Diabetes Insípido Neurogênico/genética , Humanos , Mutação , Neurofisinas/genética , Neurofisinas/metabolismo , Linhagem
12.
Am J Physiol Renal Physiol ; 321(3): F305-F321, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34282956

RESUMO

Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2+ concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2+ mobilization and extracellular Ca2+ influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.NEW & NOTEWORTHY Although V1BR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V1BR, highlights a cross talk between V1BR and V2 receptor (V2R) in the inner medullary collecting duct, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.


Assuntos
Receptores de Vasopressinas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Vasopressinas/farmacologia , Animais , Arginina Vasopressina/farmacologia , Masculino , Neurofisinas/efeitos dos fármacos , Precursores de Proteínas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/metabolismo , Vasopressinas/efeitos dos fármacos
13.
Pediatrics ; 147(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33795481

RESUMO

Arginine vasopressin (AVP)-mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP's chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.


Assuntos
Diabetes Insípido/diagnóstico , Diabetes Insípido/terapia , Síndrome de Secreção Inadequada de HAD/diagnóstico , Síndrome de Secreção Inadequada de HAD/terapia , Neurofisinas , Precursores de Proteínas , Vasopressinas , Criança , Diabetes Insípido/etiologia , Humanos , Síndrome de Secreção Inadequada de HAD/etiologia , Neurofisinas/fisiologia , Precursores de Proteínas/fisiologia , Vasopressinas/fisiologia
14.
Peptides ; 137: 170493, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33422647

RESUMO

Studies have shown that arginine-vasopressin (AVP) is an important neuropeptide regulating social behaviors. The present work aimed to detect changes in the AVP numbers and level in a valproic acid (VPA)-induced rat model of autism and the underlying mechanism of its pathogenesis. Our results indicated that infants exposed to VPA showed obviously impaired communication and repetitive behaviors with reduced number of AVP-ir cells in paraventricular nucleus (PVN) and cerebrospinal fluid (CSF). The postnatal subcutaneous injection of AVP can alleviate social preference deficits and stereotyped behaviors, accompanied with the increase of the AVP concentrations in the CSF. We concluded that AVP system was involved in etiology of VPA-induced autism-like symptoms and postnatal AVP treatment rescued the behavioral deficits,which could be a promising treatment for autism.


Assuntos
Arginina Vasopressina/genética , Transtorno Autístico/genética , Neurofisinas/genética , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Precursores de Proteínas/genética , Vasopressinas/genética , Adolescente , Animais , Arginina Vasopressina/farmacologia , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Ácido Valproico/toxicidade
15.
Pituitary ; 24(3): 400-411, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33433888

RESUMO

PURPOSE: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder characterized by childhood-onset progressive polyuria and polydipsia due to mutations in the arginine vasopressin (AVP) gene. The aim of the study was to describe the clinical and molecular characteristics of families with neurohypophyseal diabetes insipidus. METHODS: Five Portuguese families with autosomal dominant FNDI underwent sequencing of the AVP gene and the identified mutations were functionally characterized by in vitro studies. RESULTS: Three novel and two recurrent heterozygous mutations were identified in the AVP gene. These consisted of one initiation codon mutation in the signal peptide coding region (c.2T > C, p.Met1?), three missense mutations in the neurophysin II (NPII) coding region (c.154T > C, p.Cys52Arg; c.289C > G, p.Arg97Gly; and c.293G > C, p.Cys98Ser), and one nonsense mutation in the NPII coding region (c.343G > T, p.Glu115Ter). In vitro transfection of neuronal cells with expression vectors containing each mutation showed that the mutations resulted in intracellular retention of the vasopressin prohormone. Patients showed progressive symptoms of polyuria and polydipsia, but with wide variability in severity and age at onset. No clear genotype-phenotype correlation was observed. CONCLUSION: The intracellular accumulation of mutant vasopressin precursors supports the role of cellular toxicity of the mutant proteins in the etiology of the disorder and explains the progressive onset of the disorder. These findings further expand the AVP mutational spectrum in FNDI and contribute to the understanding of the molecular pathogenic mechanisms involved in FNDI.


Assuntos
Diabetes Insípido Neurogênico , Diabetes Insípido , Diabetes Mellitus , Arginina Vasopressina/genética , Diabetes Insípido Neurogênico/genética , Humanos , Mutação/genética , Neurofisinas/genética , Linhagem , Polidipsia , Poliúria , Vasopressinas/genética
16.
J Drugs Dermatol ; 19(12): 1146-1148, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33346511

RESUMO

BACKGROUND: Studies have shown oxytocin (OT) and its carrier protein neurophysin 1 are found in the epidermis. The oxytocin receptor, which is found on human fibroblasts has been shown, when activated by oxytocin, to inhibit senescence-associated secretory phenotype (SASP). SASP activation induces the release of proinflammatory cytokines which contribute to skin aging. Therefore, its inhibition by oxytocin would constitute a protective mechanism. This pilot study was designed to explore clinical evidence of oxytocin levels correlating to the skin’s appearance in subjects. METHODS: Oxytocin levels, facial photographs, and lifetime sun exposure questionnaires from six female subjects aged 48–61 years old were analyzed. A skin age score (SAS) was determined for each subject and was compared to the expected average SAS for each subject based on their age to determine a percentage in change, if any. A reduction in SAS would indicate more youthful appearing skin than the average person of that age. RESULTS: All subjects had at least some reduction in SAS score as compared to their expected score. An almost linear relationship of SAS reduction as related to OT levels was found, showing a correlation of more youthful appearing skin with higher OT levels. CONCLUSIONS: This study links previously published evidence of oxytocin’s protective role against inflammatory cytokine release in the skin with clinical evidence of OT levels correlating with SAS scores. Furthermore, it shows OT is likely inducing a protective function in the epidermis in the case of sun exposure and possibly with intrinsic aging. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5063.


Assuntos
Ocitocina/análise , Envelhecimento da Pele/efeitos da radiação , Pele/química , Face/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Neurofisinas/metabolismo , Ocitocina/metabolismo , Fotografação , Projetos Piloto , Receptores de Ocitocina/metabolismo , Pele/diagnóstico por imagem , Pele/efeitos da radiação , Luz Solar/efeitos adversos
17.
Cells ; 9(10)2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993088

RESUMO

As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in AVPR2 result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in AQP2 cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in AVPR2 and AQP2, the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.


Assuntos
Aquaporina 2/genética , Diabetes Insípido Nefrogênico/genética , Neurofisinas/genética , Precursores de Proteínas/genética , Receptores de Vasopressinas/genética , Vasopressinas/genética , Diabetes Insípido Nefrogênico/patologia , Humanos , Mutação/genética , Poliúria/genética , Poliúria/patologia , Mapas de Interação de Proteínas/genética , Processamento de Proteína Pós-Traducional/genética , Transporte Proteico/genética
18.
Best Pract Res Clin Endocrinol Metab ; 34(5): 101449, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32792133

RESUMO

Most cases of acquired central diabetes insipidus are caused by destruction of the neurohypophysis by: 1) anatomic lesions that destroy the vasopressin neurons by pressure or infiltration, 2) damage to the vasopressin neurons by surgery or head trauma, and 3) autoimmune destruction of the vasopressin neurons. Because the vasopressin neurons are located in the hypothalamus, lesions confined to the sella turcica generally do not cause diabetes insipidus because the posterior pituitary is simply the site of the axon terminals that secrete vasopressin into the bloodstream. In addition, the capacity of the neurohypophysis to synthesize vasopressin is greatly in excess of the body's needs, and destruction of 80-90% of the hypothalamic vasopressin neurons is required to produce diabetes insipidus. As a result, even large lesions in the sellar and suprasellar area generally are not associated with impaired water homeostasis until they are surgically resected. Regardless of the etiology of central diabetes insipidus, deficient or absent vasopressin secretion causes impaired urine concentration with resultant polyuria. In most cases, secondary polydipsia is able to maintain water homeostasis at the expense of frequent thirst and drinking. However, destruction of the osmoreceptors in the anterior hypothalamus that regulate vasopressin neuronal activity causes a loss of thirst as well as vasopressin section, leading to severe chronic dehydration and hyperosmolality. Vasopressin deficiency also leads to down-regulation of the synthesis of aquaporin-2 water channels in the kidney collecting duct principal cells, causing a secondary nephrogenic diabetes insipidus. As a result, several days of vasopressin administration are required to achieve maximal urine concentration in patients with CDI. Consequently, the presentation of patients with central diabetes insipidus can vary greatly, depending on the size and location of the lesion, the magnitude of trauma to the neurohypophysis, the degree of destruction of the vasopressin neurons, and the presence of other hormonal deficits from damage to the anterior pituitary.


Assuntos
Diabetes Insípido Neurogênico/etiologia , Doenças da Hipófise/complicações , Neuro-Hipófise/patologia , Aquaporina 2/metabolismo , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/epidemiologia , Lesões Encefálicas Traumáticas/terapia , Diabetes Insípido Nefrogênico/etiologia , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Neurogênico/diagnóstico , Diabetes Insípido Neurogênico/epidemiologia , Diabetes Insípido Neurogênico/terapia , Homeostase/fisiologia , Humanos , Neurofisinas/fisiologia , Doenças da Hipófise/diagnóstico , Doenças da Hipófise/epidemiologia , Doenças da Hipófise/terapia , Polidipsia/diagnóstico , Polidipsia/epidemiologia , Polidipsia/etiologia , Polidipsia/terapia , Poliúria/diagnóstico , Poliúria/epidemiologia , Poliúria/etiologia , Poliúria/terapia , Precursores de Proteínas/fisiologia , Vasopressinas/fisiologia , Equilíbrio Hidroeletrolítico/fisiologia
19.
Genes (Basel) ; 11(8)2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32752005

RESUMO

Anxiety, chronical stress, and depression during pregnancy are considered to affect the offspring, presumably through placental dysregulation. We have studied the term placentae of pregnancies clinically monitored with the Beck's Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 classed patients into an Index group (>10, n = 23) and a Control group (<10, n = 23). Cortisol concentrations in hair (HCC) were periodically monitored throughout pregnancy and delivery. Expression differences of main glucocorticoid pathway genes, i.e., corticotropin-releasing hormone (CRH), 11ß-hydroxysteroid dehydrogenase (HSD11B2), glucocorticoid receptor (NR3C1), as well as other key stress biomarkers (Arginine Vasopressin, AVP and O-GlcNAc transferase, OGT) were explored in medial placentae using real-time qPCR and Western blotting. Moreover, gene expression changes were considered for their association with HCC, offspring, gender, and birthweight. A significant dysregulation of gene expression for CRH, AVP, and HSD11B2 genes was seen in the Index group, compared to controls, while OGT and NR3C1 expression remained similar between groups. Placental gene expression of the stress-modulating enzyme 11ß-hydroxysteroid dehydrogenase (HSD11B2) was related to both hair cortisol levels (Rho = 0.54; p < 0.01) and the sex of the newborn in pregnancies perceived as stressful (Index, p < 0.05). Gene expression of CRH correlated with both AVP (Rho = 0.79; p < 0.001) and HSD11B2 (Rho = 0.45; p < 0.03), and also between AVP with both HSD11B2 (Rho = 0.6; p < 0.005) and NR3C1 (Rho = 0.56; p < 0.03) in the Control group but not in the Index group; suggesting a possible loss of interaction in the mechanisms of action of these genes under stress circumstances during pregnancy.


Assuntos
Ansiedade/genética , Depressão/genética , Placenta/metabolismo , Complicações na Gravidez/genética , Estresse Psicológico/genética , Transcriptoma , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adulto , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Cabelo/metabolismo , Humanos , Hidrocortisona/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Neurofisinas/genética , Neurofisinas/metabolismo , Gravidez , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Vasopressinas/genética , Vasopressinas/metabolismo
20.
Genomics ; 112(6): 4041-4052, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32650102

RESUMO

Transcriptome analysis of Clarias magur brain and gonads at preparatory, mature, 6 and 16 h post-GnRH injection (hpi) stages yielded 9.5 GB data with 39,738 contigs. Sequences of 45 reproductive genes were identified for the first time in C. magur along with unique and differentially expressed genes. The expression of 20 genes was validated by qRT-PCR. Upregulation of Cyp11A1, Cyp17A1 and FTZF1 genes in the 16hpi testis accompanied by the 17ß-HSD3 expression indicates testosterone (T) synthesis in response to LH surge, while reduced expression of CYP11B1 suggests a high T: 11-KT ratio. It is evident by the gene expression analysis that the inhibitory neurotransmitter GABA, altered T: 11-KT, increased testicular bile acids, and oxytocin-like neuropeptide in the male brain, appear to be involved in arresting the pulsatile motion of testicular smooth muscles. The work generates important leads for an effective induced breeding strategy for silurid catfish.


Assuntos
Encéfalo/metabolismo , Peixes-Gato/genética , Testículo/metabolismo , Animais , Peixes-Gato/metabolismo , Ácido Cólico/biossíntese , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Masculino , Neurofisinas/metabolismo , Ovário/metabolismo , RNA-Seq , Reprodução/genética , Sêmen , Testosterona/análogos & derivados , Testosterona/biossíntese , Testosterona/metabolismo , Transcriptoma , Ácido gama-Aminobutírico/metabolismo
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