BACKGROUND: Arginine vasopressin (AVP) has been reported to regulate insulin secretion and glucose homeostasis in the body. Previous study has shown that AVP and its receptor V1bR modulate insulin secretion via the hypothalamic-pituitary-adrenal axis. AVP has also been shown to enhance insulin secretion in islets, but the exact mechanism remains unclear.
RESULTS: In our study, we unexpectedly discovered that AVP could only stimulates insulin secretion from islets, but not β cells, and AVP-induced insulin secretion could be blocked by V1bR selective antagonist. Single-cell transcriptome analysis identified that V1bR is only expressed by the α cells. Further studies indicated that activation of the V1bR stimulates the α cells to secrete glucagon, which then promotes glucose-dependent insulin secretion from β cells in a paracrine way by activating GLP-1R but not GCGR on these cells.
CONCLUSIONS: Our study revealed a crosstalk between α and β cells initiated by AVP/V1bR and mediated by glucagon/GLP-1R, providing a mechanism to develop new glucose-controlling therapies targeting V1bR.

Arginine vasopressin (AVP) plays a main role in maintaining the homeostasis of fluid balance and vascular tone and in regulating the endocrine stress response in response to osmotic, hemodynamic and stress stimuli. However, the difficulty in measuring AVP limits its clinical application. Copeptin, the C-terminal part of the AVP precursor, is released in an equimolar concentration mode with AVP from the pituitary but is more stable and simple to measure. Therefore, copeptin has emerged as a promising surrogate marker of AVP with excellent potential for the diagnosis, differentiation and prognosis of various diseases in recent decades. However, its application requires further validation, especially in the pediatric population. This review focuses on the clinical value of copeptin in different pediatric diseases and the prospects for its application as a potential biomarker.

BACKGROUND: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aimed to investigate the anti-motion sickness action and inner ear-related mechanisms of atrial natriuretic peptide (ANP).
METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method.
RESULTS: Both rotational stimulus and intraperitoneal arginine vasopressin (AVP) injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells.
CONCLUSIONS: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.

Diabetes mellitus (DM) and arginine vasopressin deficiency (AVP-D) are characterized by polyuria. Marfan syndrome is an autosomal dominant disorder caused by pathogenetic variants in FBN1. Here, we report a patient with type 2 diabetes mellitus, AVP-D, and Marfan syndrome. Although the coexistence of type 2 diabetes mellitus and AVP-D is rare, for those patients with type 2 diabetes mellitus, the existence of AVP-D should be considered when polyuria is not in accordance with the blood glucose levels, especially for those with a low urine specific gravity. Specific symptoms or signs help to identify Marfan syndrome early, and genetic testing of the FBN1 pathogenetic variant helps to make a definitive diagnosis.

Arginine vasopressin (AVP) is a key contributor to heart failure (HF), but the underlying mechanisms remain unclear. In the present study, a mouse model of HF and human cardiomyocyte (HCM) cells treated with dDAVP are generated in vivo and in vitro, respectively. Hematoxylin and eosin (HE) staining is used to evaluate the morphological changes in the myocardial tissues. A colorimetric method is used to measure the iron concentration, Fe 2+ concentration and malondialdehyde (MDA) level. Western blot analysis is used to examine the protein levels of the V1a receptor (V1aR), calcineurin (CaN), nuclear factor of activated T cells isoform C3 (NFATC3), glutathione peroxidase 4 (GPX4) and acyl-CoA synthase long chain family member 4 (ACSL4). Immunoprecipitation (IP) and luciferase reporter assays are performed to determine the interaction between NFATC3 and ACSL4. Both in vivo and in vitro experiments reveal that the V1aR-CaN-NFATC3 signaling pathway and ferroptosis are upregulated in HFs, which are verified by the elevated protein levels of V1aR, CaN, NFATC3 and ACSL4; reduced GPX4 protein level; and enhanced Fe 2+ and MDA levels. We further find that inhibiting NFATC3 by suppressing the V1aR/CaN/NFATC3 pathway via V1aR/CaN inhibitors or sh-NFATC3 not only alleviates HF but also inhibits AVP-induced ferroptosis. Mechanistically, sh-NFATC3 significantly reverses the increase in AVP-induced ACSL4 protein level, Fe 2+ concentration, and MDA level by directly interacting with ACSL4. Our results demonstrate that AVP enhances ACSL4 expression by activating the V1aR/CaN/NFATC3 pathway to induce ferroptosis, thus contributing to HF. This study may lead to the proposal of a novel therapeutic strategy for HF.

In zebrafish, estrogens produced in the ovaries via Cyp19a1a activity are required for both sexual differentiation of the ovary during early development as well as maintenance of the ovarian state during adulthood. The importance of Cyp19a1b that is highly expressed in the brain for female reproduction is still under study. We previously reported that female cyp19a1b -/- mutant zebrafish have significantly lower brain estradiol levels and impaired spawning behavior characterized by an increased latency to oviposition during dyadic sexual behavior encounters. In the current study, we provide evidence that the delayed oviposition in female cyp19a1b -/- mutants is linked to impaired arginine vasopressin (Avp) signaling. Droplet digital PCR experiments revealed that levels of the estrogen receptors, avp, and oxytocin (oxt) are lower in the hypothalamus of mutant females compared to wildtype fish. We then used acute intraperitoneal injections of Avp and Oxt, along with mixtures of their respective receptor antagonists, to determine that Avp can uniquely rescue the delayed oviposition in female cyp19a1b -/- mutants. Using immunohistochemistry, we demonstrated that Cyp19a1b-expressing radial glial cell (RGC) fibers surround and are in contact with Avp-immunopositive neurons in the preoptic areas of the brain. This could provide the neuroanatomical proximity for RGC-derived estrogens to diffuse to and activate estrogen receptors and regulate avp expression levels. Together these findings identify a positive link between Cyp19a1b and Avp for female zebrafish sexual behavior. They also suggest that the female cyp19a1b -/- mutant behavioral phenotype is likely a consequence of impaired processing of Avp-dependent social cues important for mate identification and assessment.

Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules-an excretory organ that is equivalent to renal tubules4-to activate nitric oxide synthase-cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour-renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.

Arginine vasopressin (AVP) plays a hypothermic regulatory role in thermoregulation and is an important endogenous mediator in this mechanism. In the preoptic area (POA), AVP increases the spontaneous firing and thermosensitivity of warm-sensitive neurons and decreases those of cold-sensitive and temperature-insensitive neurons. Because POA neurons play a crucial role in precise thermoregulatory responses, these findings indicate that there is an association between the hypothermia and changes in the firing activity of AVP-induced POA neurons. However, the electrophysiological mechanisms by which AVP controls this firing activity remain unclear. Therefore, in the present study, using in vitro hypothalamic brain slices and whole-cell recordings, we elucidated the membrane potential responses of temperature-sensitive and -insensitive POA neurons to identify the applications of AVP or V1a vasopressin receptor antagonists. By monitoring changes in the resting potential and membrane potential thermosensitivity of the neurons before and during experimental perfusion, we observed that AVP increased the changes in the resting potential of 50% of temperature-insensitive neurons but reduced them in others. These changes are because AVP enhances the membrane potential thermosensitivity of nearly 50% of the temperature-insensitive neurons. On the other hand, AVP changes both the resting potential and membrane potential thermosensitivity of temperature-sensitive neurons, with no differences between the warm- and cold-sensitive neurons. Before and during AVP or V1a vasopressin receptor antagonist perfusion, no correlation was observed between changes in the thermosensitivity and membrane potential of all neurons. Furthermore, no correlation was observed between the thermosensitivity and membrane potential thermosensitivity of the neurons during experimental perfusion. In the present study, we found that AVP induction did not result in any changes in resting potential, which is unique to temperature-sensitive neurons. The study results suggest that AVP-induced changes in the firing activity and firing rate thermosensitivity of POA neurons are not controlled by resting potentials.

This study aims to explore the relationship between polymorphism of the arginine vasopressin (AVP) gene and plasma copeptin concentration with the occurrence of hypertension in pregnancy.
We conducted a matched nested case-control study in Chinese women. The genotypes of rs3729965, rs3761249, rs1410713, rs2740204, and rs2282018 loci of AVP gene and plasma copeptin at 16-20 gestational weeks were detected in 288 patients with gestational hypertension (GH), 82 with preeclampsia (PE), and 14 with chronic hypertension with superimposed preeclampsia (CH-PE) and their healthy matched controls.
For every natural logarithm unit increment in copeptin, the risks of GH and PE/CH-PE increased by 5.556 (adjusted odds ratio [aOR]: 6.556, 95% confidence interval [CI]: 2.734-15.717) and 3.312 times (aOR: 4.312, 95% CI: 1.168-15.914). Under the dominant model, the genotype CC + CT of rs2282018 and GG + GT of rs3761249 had higher risks of GH than genotype TT, with aORs of 1.757 (95% CI: 1.077-2.867) and 1.814 (95% CI: 1.111-2.963). Allele A of rs3729965 loci had a lower risk of PE/CH-PE than allele G (aOR: 0.441, 95% CI: 0.199-0.978). However, the frequencies of rs1410713 and rs2740204 genotypes were not significantly different between cases and controls. The model of copeptin combined with the AVP gene and traditional factors (TFs) had a higher ability than the TFs model in predicting GH and PE/CH-PE.
Our study confirms that higher plasma copeptin and AVP gene variants are associated with the occurrence of GH and PE/CH-PE. The detection of copeptin and AVP gene in the early second trimester improves the predictive ability of TFs for GH and PE/CH-PE.

Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and this could be a factor in cardiac inflammation and fibrosis. Herein, we studied the effects of AVP on interleukin-1β (IL-1β) production and the role(s) of β-arrestin2-dependent signaling in murine heart.
The levels of IL-1β mRNA and protein in adult rat cardiofibroblasts (ARCFs) was measured using quantitative PCR and ELISA, respectively. The activity of β-arrestin2 was manipulated using either pharmacologic inhibitors or through recombinant β-arrestin2 over-expression. These experiments were conducted to determine the roles of β-arrestin2 in the regulation of AVP-induced IL-1β and NLRP3 inflammasome production. The phosphorylation and activation of NF-κB induced by AVP was measured by immunoblotting. β-arrestin2 knockout (KO) mice were used to investigate whether β-arrestin2 mediated the AVP-induced production of IL-1β and NLRP3, as well as the phosphorylation of the NF-κB p65 subunitin mouse myocardium. Prism GraphPad software(version 8.0), was used for all statistical analyses.
AVP induced the expression of IL-1β in a time-dependent manner in ARCFs but not in cultured adult rat cardiomyocytes (ARCMs). The inhibition of NF-κB with pyrrolidinedithiocarbamic acid (PDTC) prevented the AVP-induced phosphorylation of NF-κB and production of IL-1β and NLRP3 in ARCFs. The deletion of β-arrestin2 blocked the phosphorylation of p65 and the expression of NLRP3 and IL-1β induced by AVP in both mouse hearts and in ARCFs.
AVP promotes IL-1β expression through β-arrestin2-mediated NF-κB signaling in murine heart.