Tamoxifen attenuates development of lithium-induced nephrogenic diabetes insipidus in rats
Tamoxifen attenuates development of lithium-induced nephrogenic diabetes insipidus in rats
复制标题
他莫昔芬可减轻锂诱导的大鼠肾性尿崩症的发展
DOI：
10.1152/ajprenal.00604.2017
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发表时间：
2018-05-01
影响因子：
4.2
通讯作者：
Norregaard, Rikke
中科院分区：
文献类型：
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作者：
Tingskov, Stine Julie;Hu, Shan;Norregaard, Rikke
锂被广泛用于治疗双相情感障碍，但经常导致肾源性尿崩症（NDI），一种以严重的尿浓缩缺陷为特征的疾病。锂诱导的NDI是由集合管主细胞的锂摄取和水通道蛋白-2（AQP2）的表达改变引起的，其对于集合管中小管流体的水重吸收是必需的。性激素以前已被证明会影响AQP2的调节，所以我们测试了他莫昔芬（TAM），一种选择性雌激素受体调节剂，是否会减弱锂诱导的肾脏水稳态的改变。用锂处理大鼠14天，并且在锂施用开始后1周开始TAM处理。锂治疗导致严重的多尿和AQP2表达减少，TAM可改善这些情况。与此相符。TAM减弱了AQP2的下调，增加了cAMP反应元件结合蛋白的磷酸化，这诱导了从锂处理大鼠制备的新鲜分离的内髓集合管悬液中AQP2的表达。总之，TAM剂量依赖性地减轻了锂诱导的NDI大鼠的多尿，损害了尿浓度和AQP2蛋白表达的下调。这些研究结果表明，TAM可能是锂诱导的NDI的一种新的治疗选择。
Lithium is widely used in treatment of bipolar affective disorders but often causes nephrogenic diabetes insipidus (NDI), a disorder characterized by severe urinary-concentrating defects. Lithium-induced NDI is caused by lithium uptake by collecting duct principal cells and altered expression of aquaporin-2 (AQP2), which are essential for water reabsorption of tubular fluid in the collecting duct. Sex hormones have previously been shown to affect the regulation of AQP2, so we tested whether tamoxifen (TAM), a selective estrogen receptor modulator, would attenuate lithium-induced alterations on renal water homeostasis. Rats were treated for 14 days with lithium, and TAM treatment was initiated 1 wk after onset of lithium administration. Lithium treatment resulted in severe polyuria and reduced AQP2 expression, which were ameliorated by TAM. Consistent with this. TAM attenuated downregulation of AQP2 and increased phosphorylation of the cAMP-responsive element-binding protein, which induced AQP2 expression in freshly isolated inner-medullary collecting duct suspension prepared from lithium-treated rats. In conclusion, TAM attenuated polyuria dose dependently and impaired urine concentration and downregulation of AQP2 protein expression in rats with lithium-induced NDI. These findings suggest that TAM is likely to be a novel therapeutic option for lithium-induced NDI.