Activating Transcription Factor 6α Is Required for the Vasopressin Neuron System to Maintain Water Balance Under Dehydration in Male Mice
Activating Transcription Factor 6α Is Required for the Vasopressin Neuron System to Maintain Water Balance Under Dehydration in Male Mice
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DOI：
10.1210/en.2014-1522
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发表时间：
2014-12-01
期刊：
影响因子：
4.8
通讯作者：
Arima, Hiroshi
中科院分区：
文献类型：
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作者：
Azuma, Yoshinori;Hagiwara, Daisuke;Arima, Hiroshi
激活转录因子 6 α (ATF6 α) 是内质网 (ER) 应激的传感器，可增加 ER 伴侣和与 ER 相关的未折叠/错误折叠蛋白降解相关分子的表达。在本研究中，我们使用ATF6α基因敲除（ATF6α(-/-)）小鼠来阐明ATF6α在精氨酸加压素（AVP）神经元系统中的作用。虽然随意饮水的 ATF6 α(-/-) 和野生型 (ATF6 α(-/-)) 小鼠之间的尿量没有差异，但与间歇性缺水 (WD) 下的 ATF6 α(-/-) 小鼠相比，ATF6 α(-/-) 小鼠的尿量有所增加，并且 ATF6 α(-/-) 小鼠的尿 AVP 较少。 WD后，ATF6 α(-/-)小鼠视上核中免疫球蛋白重链结合蛋白（一种ER伴侣）的mRNA表达显着增加，但ATF6 α(-/-)小鼠则没有。电镜分析表明，WD 后 ATF6 α(-/-) 小鼠 AVP 神经元的 ER 管腔比 ATF6 α(-/-) 小鼠扩张得更多。 ATF6 α(-/-) 小鼠与具有导致家族性神经垂体尿崩症 (FNDI) 突变的小鼠交配，其特征是由于突变 AVP 前体在 ER 中积累而导致进行性多尿和 AVP 神经元损失，在间歇性 WD 下表现出尿量增加。与FNDI小鼠相比，FNDI/ATF6α(-/-)小鼠内质网AVP神经元聚集形成进一步受损，并且WD下FNDI/ATF6α(-/-)小鼠AVP神经元损失加速。这些数据表明，AVP 神经元系统需要 ATF6 α 来维持脱水状态下的水平衡。
Activating transcription factor 6 alpha (ATF6 alpha) 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 ATF6 alpha knockout (ATF6 alpha(-/-)) mice to clarify the role of ATF6 alpha in the arginine vasopressin (AVP) neuron system. Although urine volumes were not different between ATF6 alpha(-/-) and wild-type (ATF6 alpha(-/-)) mice with access to water ad libitum, they were increased in ATF6 alpha(-/-) mice compared with those in ATF6 alpha(-/-) mice under intermittent water deprivation (WD) and accompanied by less urine AVP in ATF6 alpha(-/-) mice. The mRNA expression of immunoglobulin heavy chain binding protein, an ER chaperone, was significantly increased in the supraoptic nucleus in ATF6 alpha(-/-) but not ATF6 alpha(-/-) mice after WD. Electron microscopic analyses demonstrated that the ER lumen of AVP neurons was more dilated in ATF6 alpha(-/-) mice than in ATF6 alpha(-/-) mice after WD. ATF6 alpha(-/-) 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/ATF6 alpha(-/-) mice compared with that in FNDI mice, and AVP neuronal loss was accelerated in FNDI/ATF6 alpha(-/-) mice under WD. These data suggest that ATF6 alpha is required for the AVP neuron system to maintain water balance under dehydration.