Activating transcription factor 6α (ATF6α) is a sensor of endoplasmic reticulum (ER) stress and increases the expression of ER chaperones and molecules related to the ER-associated degradation of unfolded/misfolded proteins. In this study, we used ATF6α knockout (ATF6α-/-) mice to clarify the role of ATF6α in the arginine vasopressin (AVP) neuron system. Although urine volumes were not different between ATF6&alpha:-/- and wild-type (ATF6α+/+) mice with access to water ad libitum, they were increased in ATF6α-/- mice compared with those in ATF6α+/+ mice under intermittent water deprivation (WD) and accompanied by less urine AVP in ATF6α-/- mice. The mRNA expression of immunoglobulin heavy chain binding protein, an ER chaperone, was significantly increased in the supraoptic nucleus in ATF6α+/+ but not ATF6α-/- mice after WD. Electron microscopic analyses demonstrated that the ER lumen of AVP neurons was more dilated in ATF6α-/- mice than in ATF6α+/+ mice after WD. ATF6α-/- mice that were mated with mice possessing a mutation causing familial neurohypophysial diabetes insipidus (FNDI), which is characterized by progressive polyuria and AVP neuronal loss due to the accumulation of mutant AVP precursor in the ER, manifested increased urine volume under intermittent WD. The aggregate formation in the ER of AVP neurons was further impaired in FNDI/ATF6α-/- mice compared with that in FNDI mice, and AVP neuronal loss was accelerated in FNDI/ATF6α-/- mice under WD. These data suggest that ATF6α is required for the AVP neuron system to maintain water balance under dehydration.
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