4-PBA improves lithium-induced nephrogenic diabetes insipidus by attenuating ER stress
4-PBA improves lithium-induced nephrogenic diabetes insipidus by attenuating ER stress
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4-PBA 通过减轻 ER 应激改善锂诱导的肾性尿崩症
DOI：
10.1152/ajprenal.00225.2016
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
王蔚东
中科院分区：
文献类型：
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作者：
王蔚东
内质网(ER)应激与某些类型的肾小球和肾小管疾病有关。本研究的目的是阐明内质网应激在锂诱导的肾源性尿崩症(NDI)中的作用，并探讨4-苯丁酸(4-PBA)缓解内质网应激是否能改善锂治疗大鼠的尿液浓缩缺陷。Wistar大鼠给予锂(40 mmol/kg饲料)、4-PBA(每天320 mg/kg体重体重灌胃)或不处理(对照组)2wk，在安乐死前脱水24 h。锂盐处理可增加尿量，降低尿渗透压，而4-PBA能显著改善这一现象。4-PBA还可阻止缺锂24小时大鼠肾脏内髓水通道蛋白-2(AQP2)、pS256-AQP2和pS261-AQP2蛋白表达降低。锂处理后内髓ER应激标志物表达增加，与内髓集合管(IMCD)主细胞内池扩张和ER扩张有关。共聚焦免疫荧光研究表明，结合免疫球蛋白(Bip)的分子伴侣与AQP2在主细胞中共定位。免疫组织化学结果显示，染锂大鼠IMCD主细胞内Bip表达增加，AQP2表达降低。4-PBA可减弱内质网应激标志物的表达，恢复内质网形态。在锂处理大鼠分离的IMCD悬浮液中，4-PBA孵育也与AQP2表达增加和改善内质网应激有关。总之，在实验性锂诱导的NDI中，4-PBA改善了尿液浓缩缺陷，增加了AQP2的表达，这可能是通过减轻IMCD主细胞的内质网应激来实现的。
Endoplasmic reticulum (ER) stress has been implicated in some types of glomerular and tubular disorders. The objectives of this study were to elucidate the role of ER stress in lithium-induced nephrogenic diabetes insipidus (NDI) and to investigate whether attenuation of ER stress by 4-phenylbutyric acid (4-PBA) improves urinary concentrating defect in lithium-treated rats. Wistar rats received lithium (40 mmol/kg food), 4-PBA (320 mg/kg body wt by gavage every day), or no treatment (control) for 2 wk, and they were dehydrated for 24 h before euthanasia. Lithium treatment resulted in increased urine output and decreased urinary osmolality, which was significantly improved by 4-PBA. 4-PBA also prevented reduced protein expression of aquaporin-2 (AQP2), pS256-AQP2, and pS261-AQP2 in the inner medulla of kidneys from lithium-treated rats after 24-h dehydration. Lithium treatment resulted in increased expression of ER stress markers in the inner medulla, which was associated with dilated cisternae and expansion of ER in the inner medullary collecting duct (IMCD) principal cells. Confocal immunofluorescence studies showed colocalization of a molecular chaperone, binding IgG protein (BiP), with AQP2 in principal cells. Immunohistochemistry demonstrated increased intracellular expression of BiP and decreased AQP2 expression in IMCD principal cells of kidneys from lithium-treated rats. 4-PBA attenuated expression of ER stress markers and recovered ER morphology. In IMCD suspensions isolated from lithium-treated rats, 4-PBA incubation was also associated with increased AQP2 expression and ameliorated ER stress. In conclusion, in experimental lithium-induced NDI, 4-PBA improved the urinary concentrating defect and increased AQP2 expression, likely via attenuating ER stress in IMCD principal cells.