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

Abstract

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 ...

Mechanisms Underlying Progressive Polyuria in Familial Neurohypophysial Diabetes Insipidus

“…In the first one, female FNDI mice (which showed more progressive polyuria) were administered dDAVP subcutaneously with osmotic minipumps to decrease AVP synthesis. As expected, the dDAVP treatment significantly decreased AVP mRNA expression in the SON, accompanied by decreases in inclusion bodies in the AVP neurones (19). In the second experiment, the males were fed a high sodium diet to stimulate AVP synthesis.…”

“…In the second experiment, the males were fed a high sodium diet to stimulate AVP synthesis. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased with the high sodium diet compared to the control given a low sodium diet (19). These data suggest that, although inclusion bodies were not immunostained with antibodies for normal or mutant NPII, they were likely to be formed by mutant (and possibly normal) AVP precursors that were misfolded.…”

“…Our group also made knock‐in mice of Cys98stop that manifested increases in urine volume and water intake accompanied by decreases in urine osmolality (15). Below, we will discuss the possible mechanisms underlying progressive polyuria in FNDI based on the findings obtained in our FNDI mice (15, 19).…”

“…Although the FNDI mice compensate for polyuria by increasing water intake, they are potentially dehydrated. Indeed, when the FNDI mice were treated with dDAVP, an AVP analogue, the haematocrit levels were decreased (19). Such chronic dehydration in FNDI mice could cause both increases in plasma osmolality and decreases in blood volume, and thus would stimulate AVP synthesis and release.…”

Animal Models as Tools to Investigate Antidiabetic and Anti-Inflammatory Plants

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