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.

No abstract

Familial neurohypophysial diabetes insipidus (FNDI) is caused by mutations in the gene locus of arginine vasopressin (AVP), an antidiuretic hormone. Although the carriers are normal at birth, polyuria and polydipsia appear several months or years later. Previously, we made mice possessing a mutation causing FNDI and reported that the mice manifested progressive polyuria as do the patients with FNDI. Here, we report that decreases in AVP mRNA expression in the supraoptic nucleus were accompanied by shortening of the AVP mRNA poly(A) tail length in the FNDI mice, a case in which aggregates accumulated in the endoplasmic reticulum (ER) of the hypothalamic AVP neurons. Expression levels of AVP heteronuclear RNA in the supraoptic nucleus, a sensitive indicator for gene transcription, were not significantly different between FNDI and wild-type mice. Incubation of hypothalamic explants of wild-type mice with ER stressors (thapsigargin and tunicamycin) caused shortening of the poly(A) tail length of AVP and oxytocin mRNA, accompanied by decreases in their expression. On the other hand, an ER stress-reducing molecule (tauroursodeoxycholate) increased the poly(A) tail length as well as the expression levels of AVP and oxytocin mRNA. These data reveal a novel mechanism by which ER stress decreases poly(A) tail length of neurohypophysial hormones, probably to reduce the load of unfolded proteins.

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.hereditary disease; aggregates ARGININE VASOPRESSIN (AVP), an antidiuretic hormone, is synthesized in the magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus of the hypothalamus (2, 36). The synthesis, as well as the release of AVP, is stimulated by increases in plasma osmolality and decreases in blood volume (blood pressure) (2, 36). The process from synthesis to release includes transcription, translation of the mRNA, folding of the precursor within the endoplasmic reticulum (ER), cleavage of the precursors during axonal transport, and release of AVP into the circulation (6).AVP plays a pivotal role in the homeostasis of water balance, and a deficiency of AVP leads to diabetes insipidus (DI) characterized by polyuria (22). Familial neurohypophysial DI (FNDI) is a rare autosomal dominant disorder (23). More than 50 point mutations in FNDI have been reported in the AVP gene so far, with most mutations existing in the domain of neurophysin II (NPII) (11), which functions as a carrier protein of AVP (36). While mechanisms underlying progressive polyuria in FNDI have not yet been fully elucidated, we demonstrated recently (15) that aggregates had progressively accumulated in the ER of AVP neurons in parallel with the progressive polyuria in mice possessing a point mutation (Cys98stop) in the NPII gene, which causes FNDI in humans (26). These data suggest that the accumulations of aggregates in ER that were probably derived from AVP precursors ...

The adipocyte-derived hormone adiponectin plays an important role in modulating energy homeostasis through peripheral tissues and the central nervous system. Several studies have reported that adiponectin exists in cerebrospinal fluid and that adiponectin receptors are expressed in the hypothalamus, including the paraventricular nucleus (PVN), which plays a key role in controlling pituitary hormone secretion. Furthermore, it has been reported that magnocellular arginine vasopressin (AVP) neurones within the PVN express adiponectin receptors. These findings suggest a central role of adiponectin in the modulation of neuroendocrinological functions. In the present study, we investigated the effect of centrally-administered adiponectin on AVP release in conscious rats. Intracerebroventricular (i.c.v.) administration of adiponectin significantly reduced the basal plasma AVP concentration in a dose-dependent manner, with a maximal effect being obtained 10 min after administration. The plasma AVP increase in response to either hyperosmolar or hypovolaemic stimulation was also significantly attenuated by an i.c.v. injection of adiponectin. Treatment with AMP-activated protein kinase (AMPK) inhibitor compound C (100 nmol, i.c.v.) partially reversed the inhibitory effects of adiponectin on AVP release. These findings suggest that central adiponectin plays an inhibitory role in the osmoregulation and baroregulation of AVP release, that the AMPK pathway is at least partly involved in the action of adiponectin, and further suggest a novel physiological or pathophysiological role for central adiponectin in water balance via inhibition of AVP release.