Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus

2010 ◽  
Vol 298 (2) ◽  
pp. R486-R493 ◽  
Author(s):  
Maiko Hiroi ◽  
Yoshiaki Morishita ◽  
Masayuki Hayashi ◽  
Nobuaki Ozaki ◽  
Yoshihisa Sugimura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Diabetes Insipidus ◽  
Inclusion Bodies ◽  
Autosomal Dominant ◽  
Urine Volume ◽  
Vehicle Control ◽  
Aggregate Formation ◽  
Vasopressin Neurons ◽  
Immunohistochemical Analyses

Familial neurohypophysial diabetes insipidus (FNDI) is a rare disease that is inherited in an autosomal dominant manner. In a previous study, we made a mouse model for FNDI, which showed progressive polyuria accompanied by inclusion bodies in the arginine vasopressin (AVP) neurons formed by aggregates in the endoplasmic reticulum. The present study was conducted to determine whether the activities of AVP neurons are related to the phenotype progression in the FNDI model. In the first experiment, female heterozygous mice were administered either desmopressin (dDAVP) or a vehicle (control) subcutaneously with osmotic minipumps for 30 days. The dDAVP treatment significantly decreased the urine volume, AVP mRNA expression, and inclusion bodies in the AVP neurons. Urine volume in the dDAVP group remained significantly less than the control for 14 days even after the minipumps were removed. In the second experiment, the males were fed either a 0.2% Na or 2.0% Na diet for 6 mo. Urine AVP excretion was significantly increased in the 2.0% Na group compared with the 0.2% Na group for the first 2 mo but gradually decreased thereafter. Throughout the experiments, urine volume increased progressively in the 2.0% Na group but not in the 0.2% Na group. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased in the 2.0% Na compared with the 0.2% Na group. These data demonstrated that activation of AVP neurons could accelerate the aggregate formation as well as the progression of the polyuria in the FNDI model mice.

Progressive polyuria without vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus

2009 ◽  
Vol 296 (5) ◽  
pp. R1641-R1649 ◽  
Author(s):  
Masayuki Hayashi ◽  
Hiroshi Arima ◽  
Noriyuki Ozaki ◽  
Yoshiaki Morishita ◽  
Maiko Hiroi ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Inclusion Bodies ◽  
Urine Volume ◽  
Neuronal Loss ◽  
Wild Type ◽  
Autosomal Dominant Disorder ◽  
Electron Microscopic ◽  
Vasopressin Neuron ◽  
Immunohistochemical Analyses

Familial neurohypophysial diabetes insipidus (FNDI), an autosomal dominant disorder, is mostly caused by mutations in the gene of neurophysin II (NPII), the carrier protein of arginine vasopressin (AVP). Previous studies suggest that loss of AVP neurons might be the cause of polyuria in FNDI. Here we analyzed knockin mice expressing mutant NPII that causes FNDI in humans. The heterozygous mice manifested progressive polyuria as do patients with FNDI. Immunohistochemical analyses revealed that inclusion bodies that were not immunostained with antibodies for mutant NPII, normal NPII, or AVP were present in the AVP cells in the supraoptic nucleus (SON), and that the size of inclusion bodies gradually increased in parallel with the increases in urine volume. Electron microscopic analyses showed that aggregates existed in the endoplasmic reticulum (ER) as well as in the nucleus of AVP neurons in 1-mo-old heterozygous mice. At 12 mo, dilated ER filled with aggregates occupied the cytoplasm of AVP cells, while few aggregates were found in the nucleus. Analyses with in situ hybridization revealed that expression of AVP mRNA was significantly decreased in the SON in the heterozygous mice compared with that in wild-type mice. Counting cells expressing AVP mRNA in the SON indicated that polyuria had progressed substantially in the absence of neuronal loss. These data suggest that cell death is not the primary cause of polyuria in FNDI, and that the aggregates accumulated in the ER might be involved in the dysfunction of AVP neurons that lead to the progressive polyuria.

scholarly journals Differential Cellular Handling of Defective Arginine Vasopressin (AVP) Prohormones in Cells Expressing Mutations of the AVP Gene Associated with Autosomal Dominant and Recessive Familial Neurohypophyseal Diabetes Insipidus

2004 ◽  
Vol 89 (9) ◽  
pp. 4521-4531 ◽  
Author(s):  
Jane H. Christensen ◽  
Charlotte Siggaard ◽  
Thomas J. Corydon ◽  
Gary L. Robertson ◽  
Niels Gregersen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Amino Acid ◽  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Autosomal Dominant ◽  
Autosomal Dominant Inheritance ◽  
Laser Scanning Microscopy ◽  
Recessive Mutation ◽  
Dominant Inheritance ◽  
Avp Gene

An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.

scholarly journals Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yohei Kawaguchi ◽  
Daisuke Hagiwara ◽  
Takashi Miyata ◽  
Yuichi Hodai ◽  
Junki Kurimoto ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Arginine Vasopressin ◽  
Urine Volume ◽  
Neuronal Loss ◽  
Protective Role ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Vasopressin Neurons

AbstractThe immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

scholarly journals Congenital nephrogenic diabetes insipidus accompanied with central nephrogenic diabetes secondary to pituitary surgery -a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Zhang ◽  
Yimin Shen ◽  
Yuezhong Ren ◽  
Yvbo Xin ◽  
Lijun Wang
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Direct Detection ◽  
Urine Volume ◽  
Pituitary Surgery ◽  
Accurate Method ◽  
Heterozygous Mutation ◽  
Case Presentation ◽  
Congenital Nephrogenic Diabetes Insipidus

Abstract Background Diabetes insipidus (DI) can be a common cause of polydipsia and polyuria. Here, we present a case of congenital nephrogenic diabetes insipidus (CNDI) accompanied with central diabetes insipidus (CDI) secondary to pituitary surgery. Case presentation A 24-year-old Chinese woman came to our hospital with the complaints of polydipsia and polyuria for 6 months. Six months ago, she was detected with pituitary apoplexy, and thereby getting pituitary surgery. However, the water deprivation test demonstrated no significant changes in urine volume and urine gravity in response to fluid depression or AVP administration. In addition, the genetic results confirmed a heterozygous mutation in arginine vasopressin receptor type 2 (AVPR2) genes. Conclusions She was considered with CNDI as well as acquired CDI secondary to pituitary surgery. She was given with hydrochlorothiazide (HCTZ) 25 mg twice a day as well as desmopressin (DDAVP, Minirin) 0.1 mg three times a day. There is no recurrence of polyuria or polydipsia observed for more than 6 months. It can be hard to consider AVPR2 mutation in female carriers, especially in those with subtle clinical presentation. Hence, direct detection of DNA sequencing with AVPR2 is a convenient and accurate method in CNDI diagnosis.

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