title: 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.
authors.affiliation: Department of Endocrinology and Diabetes, Field of Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ozaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Maiko
authors.initials: M
authors.lastname: Hiroi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagasaki
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.forename: Akira
authors.initials: A
authors.lastname: Shiota
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000235:genetics / Q000378:metabolism*; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D020790:Diabetes Insipidus, Neurogenic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004326:Drinking / Q000502:physiology; D004435:Eating / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D011141:Polyuria / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013495:Supraoptic Nucleus / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D001127:Arginine Vasopressin; D002097:C-Reactive Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000099153:Pentraxins