Mechanisms Underlying Progressive Polyuria in Familial Neurohypophysial Diabetes Insipidus

Arima, Hiroshi; Oiso, Yutaka

doi:10.1111/j.1365-2826.2010.02028.x

Cited by 11 publications

(11 citation statements)

References 22 publications

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“…Here we propose that the increased demand for protein synthesis in AVP MCNs of the hypothalamus during hypertonic stress leads to disturbances in ER homeostasis [ 30 , 31 ] and thus activation of ER stress and UPR pathway [ 7 ]. Few studies have described ER stress responses in MCNs of hypothalamus under physiological conditions [ 23 ], but ER stress is believed to be involved in the pathogenesis of familial neurohypophyseal diabetes insipidus (FNDI), a progressive neurodegenerative disease caused by mutations of AVP gene which results in symptoms of polyuria and polydipsia [ 32 , 33 ]. These mutations interfere with the folding of the AVP precursor protein in MCNs of hypothalamus, resulting in retention of the mutant precursor in the ER lumen [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus

Greenwood

Paton

et al. 2015

PLoS ONE

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Arginine vasopressin (AVP) is synthesised in magnocellular neurons (MCNs) of supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. In response to the hyperosmotic stressors of dehydration (complete fluid deprivation, DH) or salt loading (drinking 2% salt solution, SL), AVP synthesis increases in MCNs, which over-burdens the protein folding machinery in the endoplasmic reticulum (ER). ER stress and the unfolded protein response (UPR) are signaling pathways that improve ER function in response to the accumulation of misfold/unfold protein. We asked whether an ER stress response was activated in the SON and PVN of DH and SL rats. We observed increased mRNA expression for the immunoglobulin heavy chain binding protein (BiP), activating transcription factor 4 (Atf4), C/EBP-homologous protein (Chop), and cAMP responsive element binding protein 3 like 1 (Creb3l1) in both SON and PVN of DH and SL rats. Although we found no changes in the splicing pattern of X box-binding protein 1 (Xbp1), an increase in the level of the unspliced form of Xbp1 (Xbp1U) was observed in DH and SL rats. CREB3L1, a novel ER stress inducer, has been shown to be activated by ER stress to regulate the expression of target genes. We have previously shown that CREB3L1 is a transcriptional regulator of the AVP gene; however, a role for CREB3L1 in the response to ER stress has yet to be investigated in MCNs. Here, we used lentiviral vectors to introduce a dominant negative form of CREB3L1 (CREB3L1DN) in the rat SON. Expression of CREB3L1DN in the SON decreased Chop and Xbp1U mRNA levels, but not BiP and Atf4 transcript expression. CREB3L1 is thus implicated as a transcriptional mediator of the ER stress response in the osmotically stimulated SON.

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Section: Discussionmentioning

confidence: 99%

Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus

Greenwood

Paton

et al. 2015

PLoS ONE

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“…3 There are several lines of evidence to suggest that the mutant AVP precursors are trapped in the ER, 4, 5, 6 and our previous studies demonstrated that inclusion bodies were formed in the lumen of ER in a FNDI mouse model. 7, 8 The accumulation of aggregates in the ER would finally lead to cellular loss of AVP neurons, as previous autopsy studies reported AVP neuronal loss in the hypothalamus of patients with FNDI.…”

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confidence: 95%

Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus

et al. 2014

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Familial neurohypophysial diabetes insipidus (FNDI) characterized by progressive polyuria is mostly caused by mutations in the gene encoding neurophysin II (NPII), which is the carrier protein of the antidiuretic hormone, arginine vasopressin (AVP). Although accumulation of mutant NPII in the endoplasmic reticulum (ER) could be toxic for AVP neurons, the precise mechanisms of cell death of AVP neurons, reported in autopsy studies, remain unclear. Here, we subjected FNDI model mice to intermittent water deprivation (WD) in order to promote the phenotypes. Electron microscopic analyses demonstrated that, while aggregates are confined to a certain compartment of the ER in the AVP neurons of FNDI mice with water access ad libitum, they were scattered throughout the dilated ER lumen in the FNDI mice subjected to WD for 4 weeks. It is also demonstrated that phagophores, the autophagosome precursors, emerged in the vicinity of aggregates and engulfed the ER containing scattered aggregates. Immunohistochemical analyses revealed that expression of p62, an adapter protein between ubiquitin and autophagosome, was elicited on autophagosomal membranes in the AVP neurons, suggesting selective autophagy induction at this time point. Treatment of hypothalamic explants of green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice with an ER stressor thapsigargin increased the number of GFP-LC3 puncta, suggesting that ER stress could induce autophagosome formation in the hypothalamus of wild-type mice as well. The cytoplasm of AVP neurons in FNDI mice was occupied with vacuoles in the mice subjected to WD for 12 weeks, when 30–40% of AVP neurons are lost. Our data thus demonstrated that autophagy was induced in the AVP neurons subjected to ER stress in FNDI mice. Although autophagy should primarily be protective for neurons, it is suggested that the organelles including ER were lost over time through autophagy, leading to autophagy-associated cell death of AVP neurons.

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“…Two mechanisms have been suggested for NPII-induced polyuria, which has been demonstrated to involve mutant AVP proteins detained in the endoplasmic reticulum, and aggregation of mutant proteins may exhibit a cytotoxic effect, leading to further depletion of neuronal AVP cells and apoptosis in patients with FNDI (8). Alternatively, mutant NPII may cause polyuria, suggesting a dominant negative regulation of mutant NPII proteins (20,21). It should be noted that although cell death is not the primary cause of progressive polyuria, it may lead to neuronal depletion (21).…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, mutant NPII may cause polyuria, suggesting a dominant negative regulation of mutant NPII proteins (20,21). It should be noted that although cell death is not the primary cause of progressive polyuria, it may lead to neuronal depletion (21). Hence, the mechanisms underlying apoptosis induced by the aggregation of mutant AVP precursors in the endoplasmic reticulum merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

Identification of five novel arginine vasopressin gene mutations in patients with familial neurohypophyseal diabetes insipidus

Tian

Cen

Nie

et al. 2016

International Journal of Molecular Medicine

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Familial neurohypophyseal diabetes insipidus (FNDI) is a genetic disorder presenting with polyuria and polydipsia and is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. The clinical manifestations of this disorder vary greatly depending on different mutations. The present study reports the genetic, clinical and biochemical characteristics of patients with FNDI caused by five novel mutations. Ten patients encompassing two pedigrees and four individual cases diagnosed with FNDI were included. Biochemical markers and magnetic resonance imaging (MRI) were evaluated and genomic DNA was sequenced. The results revealed that age at onset ranged from 1.0 to 11.0 years. Daily urine volumes ranged from 2.0 to 12.0 liters. One patient had mental retardation and three patients had puberty retardation; one patient had nausea, vomiting and mental retardation; and two patients had fever. Treatments, if given, included desmopressin and vasopressin tannate. Posterior pituitary T1-weighted MRI high-intensity signals were absent in two cases and present in four cases. Sequencing revealed five novel mutations in the AVP-NPII gene. On the whole, the findings of the present study indicate that FNDI exhibits different clinical manifestations and a diverse age at onset. Posterior pituitary MRI does not provide a definite diagnosis of FNDI. We also identified five novel AVP-NPII mutations. Thus, an enhanced understanding of FNDI pathogenesis may provide a basis for the development of presymptomatic FNDI diagnotic tools.

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Mechanisms Underlying Progressive Polyuria in Familial Neurohypophysial Diabetes Insipidus

Cited by 11 publications

References 22 publications

Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus

Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus

Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus

Identification of five novel arginine vasopressin gene mutations in patients with familial neurohypophyseal diabetes insipidus

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