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The American Journal of Case Reports May 2024BACKGROUND Nephrogenic diabetes insipidus (NDI) is a rare renal disorder that can be congenital, and is caused by mutations in either aquaporin 2 or arginine vasopressin...
A Rare Case of Congenital Nephrogenic Diabetes Insipidus Associated with Aquaporin 2 Gene Mutation and Subsequent Acute Lymphoblastic Leukemia: Impact of Steroids on Kidney Function.
BACKGROUND Nephrogenic diabetes insipidus (NDI) is a rare renal disorder that can be congenital, and is caused by mutations in either aquaporin 2 or arginine vasopressin receptor 2, or it can be secondary to kidney disease or electrolyte imbalance. The clinical signs of NDI include polyuria, compensatory polydipsia, hypernatremic dehydration, and growth retardation without prompt treatment. In this report, we present the case of a patient with congenital NDI who was later diagnosed with acute lymphoblastic leukemia (ALL). With dexamethasone treatment, he had uncontrolled polyuria and polydipsia. Our aim was to concentrate on the impact of steroids on the kidneys. CASE REPORT Our patient presented at the age of 9 months with signs of severe dehydration that were associated with polyuria. His laboratory examinations revealed hypernatremia and decreased urine osmolality. He was diagnosed with NDI and his exome sequence revealed a homozygous mutation at the nucleotide position AQP2 NM_000486.6: c.374C>T (p.Thr125Met). He was treated with hydrochlorothiazide and amiloride. Then, at age 19 months, he presented with gastroenteritis and a complete blood count (CBC) showed high white blood cell count and blast cells. He was diagnosed with (ALL) and began receiving chemotherapy, during which again developed polydipsia and polyuria, which could not be controlled with an increased dosage of hydrochlorothiazide. CONCLUSIONS We report a rare case of NDI caused by a missense mutation in the aquaporin 2 gene. One year later, the child developed ALL, and treatment with dexamethasone led to an uncompensated state of polydipsia and polyuria.
Topics: Humans; Male; Diabetes Insipidus, Nephrogenic; Aquaporin 2; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Infant; Dexamethasone; Mutation; Glucocorticoids
PubMed: 38769718
DOI: 10.12659/AJCR.943597 -
The Journal of Pain May 2024Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While...
Identification of Arginine-Vasopressin Receptor 1a (Avpr1a/Avpr1a) as a Novel Candidate Gene for Chronic Visceral Pain Sheds Light on the Potential Role of Enteric Neurons in the Development of Visceral Hypersensitivity.
Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of arginine-vasopressin receptor 1A (Avpr1a) as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS. Comparing 2 C57BL/6 (BL/6) substrains (C57BL/6NTac and C57BL/6J) revealed differential susceptibility to the development of chronic VH following intrarectal zymosan instillation, a validated preclinical model for postinflammatory IBS. Using whole-genome sequencing, we identified a single-nucleotide polymorphism differentiating the 2 strains in the 5' intergenic region upstream of Avpr1a, encoding the protein Avpr1a. We used behavioral, histological, and molecular approaches to identify distal colon-specific gene expression and neuronal hyperresponsiveness covarying with Avpr1a genotype and VH susceptibility. While the 2 BL/6 substrains did not differ across other gastrointestinal phenotypes (eg, fecal water retention), VH-susceptible BL/6NTac mice had higher colonic Avpr1a mRNA and protein expression. These results parallel findings that patients' colonic Avpr1a mRNA expression corresponded to higher pain ratings. Moreover, neurons of the enteric nervous system were hyperresponsive to the Avpr1a agonist arginine-vasopressin, suggesting a role for enteric neurons in the pathology underlying VH. Taken together, these findings implicate differential regulation of Avpr1a as a novel mechanism of VH susceptibility as well as a potential therapeutic target specific to VH. PERSPECTIVE: This article presents evidence of Avpr1a as a novel candidate gene for VH in a mouse model of IBS. Avpr1a genotype and/or tissue-specific expression represents a potential biomarker for chronic abdominal pain susceptibility.
PubMed: 38768798
DOI: 10.1016/j.jpain.2024.104572 -
BioRxiv : the Preprint Server For... May 2024Oxytocin is a neuropeptide thought to play a central role in regulating social and emotional behavior. Current techniques for neuropeptide imaging are generally limited...
Oxytocin is a neuropeptide thought to play a central role in regulating social and emotional behavior. Current techniques for neuropeptide imaging are generally limited in spatial and temporal resolution, real-time imaging capacity, selectivity for oxytocin over vasopressin, and application in young and non-model organisms. To avoid the use of endogenous oxytocin receptors for oxytocin probe development, we employed a protocol to evolve purely synthetic molecular recognition on the surface of near-infrared fluorescent single-walled carbon nanotubes (SWCNT) using single-stranded DNA (ssDNA). This probe reversibly undergoes up to a 172% fluorescence increase in response to oxytocin with a K of 4.93 μM. Furthermore, this probe responds selectively to oxytocin over oxytocin analogs, receptor agonists and antagonists, and most other neurochemicals. Lastly, we show our probe can image synaptic evoked oxytocin release in live mouse brain slices. Optical probes with the specificity and resolution requisite to image endogenous oxytocin signaling can advance the study of oxytocin neurotransmission for its role in both health and disease.
PubMed: 38766215
DOI: 10.1101/2024.05.10.593556 -
Proceedings of the National Academy of... May 2024Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVP) mediate sex-biased social behaviors across most species, including mammals. In mice,...
Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVP) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth ( embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVP neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVP neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVP neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVP neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVP sex differentiation, which is impacted by prenatal BPA exposure.
Topics: Animals; Benzhydryl Compounds; Phenols; Female; Male; Mice; Sex Differentiation; Neurons; Pregnancy; Hypothalamus; Neurogenesis; Arginine Vasopressin; Vasopressins; Prenatal Exposure Delayed Effects; Paraventricular Hypothalamic Nucleus; Mice, Inbred C57BL; Estrogens
PubMed: 38753512
DOI: 10.1073/pnas.2313207121 -
ACS Pharmacology & Translational Science May 2024Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease first reported over a century ago, but its management still poses an unmet...
Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease first reported over a century ago, but its management still poses an unmet challenge. A therapeutic agent found to stabilize the condition is a short cyclic peptide, vasopressin analogue, terlipressin (TP). While TP is commonly prescribed for HRS patients in most parts of the world, it was only recently approved for use in the United States. TP exhibits short circulation half-lives and adverse side effects associated with the dose required. Herein, we present a 1,18-octadecanedioic acid (ODDA) conjugate of the cyclic peptide (ODDA-TP), which enables noncovalent binding to serum albumin native fatty acid binding modes. ODDA-TP is demonstrated to outperform TP alone in studies including cellular receptor activation, stability in plasma, pharmacokinetics, and performance in rats. Specifically, ODDA-TP had an elimination half-life 20 times that of TP alone while exhibiting a superior safety profile.
PubMed: 38751631
DOI: 10.1021/acsptsci.3c00305 -
PloS One 2024Loss-of-function mutations in the type 2 vasopressin receptor (V2R) are a major cause of congenital nephrogenic diabetes insipidus (cNDI). In the context of partial...
Loss-of-function mutations in the type 2 vasopressin receptor (V2R) are a major cause of congenital nephrogenic diabetes insipidus (cNDI). In the context of partial cNDI, the response to desmopressin (dDAVP) is partially, but not entirely, diminished. For those with the partial cNDI, restoration of V2R function would offer a prospective therapeutic approach. In this study, we revealed that OPC-51803 (OPC5) and its structurally related V2R agonists could functionally restore V2R mutants causing partial cNDI by inducing prolonged signal activation. The OPC5-related agonists exhibited functional selectivity by inducing signaling through the Gs-cAMP pathway while not recruiting β-arrestin1/2. We found that six cNDI-related V2R partial mutants (V882.53M, Y1283.41S, L1614.47P, T2736.37M, S3298.47R and S3338.51del) displayed varying degrees of plasma membrane expression levels and exhibited moderately impaired signaling function. Several OPC5-related agonists induced higher cAMP responses than AVP at V2R mutants after prolonged agonist stimulation, suggesting their potential effectiveness in compensating impaired V2R-mediated function. Furthermore, docking analysis revealed that the differential interaction of agonists with L3127.40 caused altered coordination of TM7, potentially contributing to the functional selectivity of signaling. These findings suggest that nonpeptide V2R agonists could hold promise as potential drug candidates for addressing partial cNDI.
Topics: Receptors, Vasopressin; Humans; HEK293 Cells; Diabetes Insipidus, Nephrogenic; Mutation; Signal Transduction; Cyclic AMP; Deamino Arginine Vasopressin; beta-Arrestins; Animals
PubMed: 38748623
DOI: 10.1371/journal.pone.0303507 -
Peptides Aug 2024Arginine vasotocin (AVT) is produced mainly in the hypothalamus and as a neurohypophyseal hormone peripherally regulates water-mineral balance in sub-mammals. In...
Intraperitoneal administration of arginine vasotocin (AVT) induces anorexigenic and anxiogenic actions via the brain V1a receptor-signaling pathway in the tiger puffer, Takifugu rubripes.
Arginine vasotocin (AVT) is produced mainly in the hypothalamus and as a neurohypophyseal hormone peripherally regulates water-mineral balance in sub-mammals. In addition, AVT-containing neurons innervate several areas of the brain, and AVT also acts centrally as both an anorexigenic and anxiogenic factor in goldfish. However, it is unclear whether these central effects operate in fish in general. In the present study, therefore, we investigated AVT-like immunoreactivity in the brain of the tiger puffer, a cultured fish with a high market value in Japan and also a representative marine teleost species, focusing particularly on whether AVT affects food intake and psychomotor activity. AVT-like immunoreactivity was distributed higher in the ventral region of the telencephalon, the hypothalamus and midbrain. Intraperitoneal (IP) administration of AVT at 100 pmol g body weight (BW) increased the immunoreactivity of phosphorylated ribosomal proteinS6 (RPS6), a neuronal activation marker, in the telencephalon and diencephalon, decreased food consumption and enhanced thigmotaxis. AVT-induced anorexigenic and anxiogenic actions were blocked by IP co-injection of a V1a receptor (V1aR) antagonist, Manning compound (MC) at 300 pmol g BW. These results suggest that AVT acts as an anorexigenic and anxiogenic factor via the V1aR-signaling pathway in the tiger puffer brain.
Topics: Animals; Vasotocin; Receptors, Vasopressin; Signal Transduction; Takifugu; Injections, Intraperitoneal; Brain; Eating; Anxiety; Telencephalon
PubMed: 38723948
DOI: 10.1016/j.peptides.2024.171239 -
BioRxiv : the Preprint Server For... Apr 2024The lateral septum (LS) is a midline, subcortical structure, which regulates social behaviors that are frequently impaired in neurodevelopmental disorders including...
The lateral septum (LS) is a midline, subcortical structure, which regulates social behaviors that are frequently impaired in neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Mouse studies have identified neuronal populations within the LS that express a variety of molecular markers, including vasopressin receptor, oxytocin receptor, and corticotropin releasing hormone receptor, that control specific facets of social behavior. Despite its critical role in the regulation of social behavior and notable gene expression patterns, comprehensive molecular profiling of the human LS has not been performed. Here, we conducted single nucleus RNA-sequencing (snRNA-seq) to generate the first transcriptomic profiles of the human LS using postmortem human brain tissue samples from 3 neurotypical donors. Our analysis identified 4 transcriptionally distinct neuronal cell types within the human LS that are enriched for , the gene encoding Trp-related protein 4. Differential expression analysis revealed a distinct LS neuronal cell type that is enriched for , the gene encoding the μ-opioid receptor. Leveraging recently collected mouse LS snRNA-seq datasets, we also conducted a cross-species analysis. Our results demonstrate that enrichment in the LS is highly conserved between human and mouse, while which encodes FRAS1 related extracellular matrix protein 2, is enriched only in the human LS. Together, these results highlight transcriptional heterogeneity of the human LS, and identify robust marker genes for the human LS.
PubMed: 38712125
DOI: 10.1101/2024.04.22.590602 -
Heart and Vessels May 2024Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output,...
BACKGROUND
Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output, respectively. Therefore, the treatment of HF due to severe AS complicated with AF is anticipated to be difficult. Tolvaptan, a vasopressin V2 receptor inhibitor, is effective in controlling acute decompensated heart failure (ADHF) with hemodynamic stability. However, its clinical efficacy against ADHF caused by AS with AF remains to be determined.
METHODS
Clinical information (from September 2014 to December 2017) of 59 patients diagnosed with ADHF due to severe AS (20 patients with AF; 39 patients with sinus rhythm [SR]) was obtained from the LOHAS registry. The registry collected data from seven hospitals and assessed the short-term effects of tolvaptan in patients hospitalized for ADHF with severe AS. We attempted to identify clinical differences from baseline up to 4 days, comparing patients with AF (AF group) versus those with SR (SR group).
RESULTS
There were no significant differences between the groups in age (83.7 ± 4.5 vs. 85.8 ± 6.9 years, respectively; p = 0.11) and aortic valve area (0.60 [0.46-0.73] vs. 0.56 [0.37-0.70] cm, respectively; p = 0.50). However, left atrial volume was larger (104 [85-126] vs. 87 [64-103] mL, respectively; p < 0.01), whereas stroke volume was lower (51.6 ± 14.8 vs. 59.0 ± 18.7 mL, respectively; p = 0.08) in the AF group versus the SR group. Body weight decreased daily from baseline up to day 4 in both groups (from 55.4 to 53.2 kg [p < 0.01] and from 53.5 to 51.0 kg [p < 0.01], respectively) without change in heart rate. Notably, the systolic blood pressure decreased slightly in the AF group after 2 days of treatment with tolvaptan.
CONCLUSIONS
Short-term treatment with tolvaptan improved HF in patients hospitalized for severe AS, regardless of the presence of AF or SR. After achieving sufficient diuresis, a slight decrease in blood pressure was observed in the AF group, suggesting an appropriate timeframe for safe and effective use of tolvaptan.
PubMed: 38710808
DOI: 10.1007/s00380-024-02397-3 -
Proceedings of the National Academy of... May 2024One of the largest sex differences in brain neurochemistry is the expression of the neuropeptide arginine vasopressin (AVP) within the vertebrate brain, with males...
One of the largest sex differences in brain neurochemistry is the expression of the neuropeptide arginine vasopressin (AVP) within the vertebrate brain, with males having more AVP cells in the bed nucleus of the stria terminalis (BNST) than females. Despite the long-standing implication of AVP in social and anxiety-like behaviors, the circuitry underlying AVP's control of these behaviors is still not well defined. Using optogenetic approaches, we show that inhibiting AVP BNST cells reduces social investigation in males, but not in females, whereas stimulating these cells increases social investigation in both sexes, but more so in males. These cells may facilitate male social investigation through their projections to the lateral septum (LS), an area with the highest density of sexually differentiated AVP innervation in the brain, as optogenetic stimulation of BNST AVP → LS increased social investigation and anxiety-like behavior in males but not in females; the same stimulation also caused a biphasic response of LS cells ex vivo. Blocking the vasopressin 1a receptor (V1aR) in the LS eliminated all these responses. Together, these findings establish a sexually differentiated role for BNST AVP cells in the control of social investigation and anxiety-like behavior, likely mediated by their projections to the LS.
Topics: Animals; Female; Male; Mice; Anxiety; Arginine Vasopressin; Behavior, Animal; Mice, Inbred C57BL; Neurons; Optogenetics; Receptors, Vasopressin; Septal Nuclei; Social Behavior
PubMed: 38709918
DOI: 10.1073/pnas.2319641121