Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus
Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus
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阿利吉仑可增加水通道蛋白 2 的表达并减轻锂诱导的肾性尿崩症
DOI：
10.1152/ajprenal.00553.2016
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Wang Weidong
中科院分区：
文献类型：
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作者：
Lin Yu;Zhang Tiezheng;Feng Pinning;Qiu Miaojuan;Liu Qiaojuan;Li Suchun;Zheng Peili;Kong Yonglun;Levi Moshe;Li Chunling;Wang Weidong
直接肾素抑制剂阿利吉伦已被证明即使在停止治疗后仍保留并持续存在于髓集合管中，这表明该药物有新的作用机制。本研究的目的是探讨阿利吉仑是否能调节集合管中肾水通道蛋白的表达，改善锂所致的小鼠尿浓缩缺陷。饲喂普通饲料或氯化锂饲料(40 mmo.kg干粮−1·day−1，连续4天；20 mmol.kg干粮−1·day−1，最后3天)，连续7天。部分小鼠腹腔注射阿利吉仑(50 mg·kg-1体重，−1d，−1in生理盐水)。阿利吉仑显著增加小鼠肾内髓质水通道蛋白-2(AQP2)的蛋白丰度。在内髓集合管细胞悬液中，阿利吉仑显著增加AQP2和丝氨酸256位AQP2的磷酸化(pS256-AQP2)蛋白丰度，这一作用可被腺酰环化酶抑制剂MDL-12330A和PKA抑制剂H89显著抑制，表明cAMP-PKA信号通路参与了阿利吉伦诱导的AQP2表达增加。阿利吉仑治疗改善了锂中毒小鼠的尿液浓缩缺陷，并部分阻止了肾脏内髓中AQP2和pS256-AQP2蛋白丰度的下降。结论：直接肾素抑制剂阿利吉伦上调内髓集合管主细胞AQP2蛋白表达，并可能通过cAMP-PKA通路预防锂诱导的肾源性尿崩症。
The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food−1·day−1for 4 days and 20 mmol·kg dry food−1·day−1for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt−1·day−1in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.