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

Abstract

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.

GABA Type B Receptor Signaling in Proopiomelanocortin Neurons Protects Against Obesity, Insulin Resistance, and Hypothalamic Inflammation in Male Mice on a High-Fat Diet

“…Mice were killed at the age of 16 weeks in the light cycle between 09:00 and 10:00 A.M., when they were in the fed state, and the brains were rapidly dissected and frozen. In situ hybridization was performed as described previously (Hayashi et al, 2009). The RNA probes were generated from the plasmids of POMC (Sato et al, 2007).…”

“…Tissues dissected were frozen immediately in liquid nitrogen. Whole-cell lysates were prepared in a buffer containing 10 mM Tris, pH 7.4, 50 mM NaF, 150 mM NaCl, 0.1% SDS, 2 mM Na 3 VO 4 , 5 mM EDTA, and 1% Triton X-100 (SigmaAldrich) containing fresh protease inhibitors (Rosch), and Western blot was performed as described previously (Ito et al, 2012). Membranes are incubated with GABA B R antibody (Haller et al, 2004).…”

“…POMC manifests its effects on energy balance via ␣-melanocyte-stimulating hormone (␣-MSH) and ␤-MSH, which are cleaved from POMC precursors and bind to melanocortin type 3 and 4 receptors (Harrold et al, 2003;Coll et al, 2004). A pivotal role for POMC neurons in energy homeostasis is supported by several studies; central injection of ␣-MSH or ␤-MSH decreases food intake (Fan et al, 1997;Jonsson et al, 2001;Honda et al, 2012), whereas the injection of a melanocortin receptor antagonist increases food intake in rodents (Fan et al, 1997;Aizawa-Abe et al, 2000;Obici et al, 2001;Nogueiras et al, 2007); whole-body knock-out (KO) mice for POMC (Yaswen et al, 1999) as well as those for melanocortin type 4 receptors showed obesity (Huszar et al, 1997). Previous studies also revealed that POMC neuron-specific deletion of leptin receptors (Balthasar et al, 2004) or molecules related to leptin signaling (Kievit et al, 2006;Xu et al, 2007;Banno et al, 2010) leads to obesity in mice.…”

Central Diabetes Insipidus

“…31) The analyses of animal models for FNDI have demonstrated that accumulation of mutant AVP precursors in the endoplasmic reticulum (ER) causes ER stress and dysfunction of the neurons, which finally lead to loss of AVP neurons. [31][32][33] This is consistent with autopsy studies which showed that magnocellular neurons were lost in patients with FNDI. 34) TREATMENT Desmopressin, an analogue of AVP, is used for the treatment of CDI.…”

Central Diabetes Insipidus

“…[31][32][33] This is consistent with autopsy studies which showed that magnocellular neurons were lost in patients with FNDI. 34) TREATMENT Desmopressin, an analogue of AVP, is used for the treatment of CDI.…”