Marples D, Christensen S, Christensen E I, Ottosen P D, Nielsen S
Department of Cell Biology, University of Aarhus, Denmark.
J Clin Invest. 1995 Apr;95(4):1838-45. doi: 10.1172/JCI117863.
Lithium, a widely used treatment for bipolar affective disorders, often causes nephrogenic diabetes insipidus. The effect of chronic lithium therapy on the expression of the vasopressin-regulated water channel Aquaporin-2 (AQP2) in rat kidney was examined. Membranes were prepared from inner medulla of one kidney from each rat, while the contralateral one was fixed for immunofluorescence and immunoelectronmicroscopy. Immunoblotting revealed that lithium treatment reduced AQP2 expression dramatically, to 31 +/- 8% after 10 d and to 4 +/- 1% after 25 d, coincident with development of severe polyuria. Immunofluorescence and immunogold quantitation confirmed the lithium-induced decrease in AQP2 expression (from 11.2 +/- 1.0 to 1.1 +/- 0.2 particles/microns 2). The downregulation was only partly reversed by return to lithium-free diet for 1 wk (40 +/- 8% of control). Furthermore, immunoblotting and immunogold quantitation revealed that 2 d of thirsting or 7 d of dDAVP treatment, in the continued presence of lithium, increased AQP2 expression by six- and threefold, respectively, coincident with increased urinary osmolality. Thirsting increased AQP2 immunolabeling mainly of vesicles, whereas dDAVP caused accumulation of AQP2 predominantly in the subapical region and plasma membrane. Thus, lithium causes marked downregulation of AQP2 expression, only partially reversed by cessation of therapy, thirsting or dDAVP treatment, consistent with clinical observations of slow recovery from lithium-induced urinary concentrating defects.
锂是一种广泛用于治疗双相情感障碍的药物，常导致肾性尿崩症。本研究检测了慢性锂治疗对大鼠肾脏中血管加压素调节的水通道水通道蛋白-2（AQP2）表达的影响。从每只大鼠的一侧肾脏内髓质制备膜，而对侧肾脏则固定用于免疫荧光和免疫电子显微镜检查。免疫印迹显示，锂治疗显著降低了AQP2的表达，10天后降至31±8%，25天后降至4±1%，这与严重多尿的发生相一致。免疫荧光和免疫金定量证实了锂诱导的AQP2表达降低（从11.2±1.0降至1.1±0.2颗粒/μm2）。停用锂饮食1周后，下调仅部分逆转（为对照的40±8%）。此外，免疫印迹和免疫金定量显示，在持续使用锂的情况下，2天的禁水或7天的去氨加压素（dDAVP）治疗分别使AQP2表达增加了6倍和3倍，这与尿渗透压升高相一致。禁水主要增加了囊泡的AQP2免疫标记，而dDAVP导致AQP2主要在顶端下区域和质膜积累。因此，锂导致AQP2表达显著下调，仅通过停止治疗、禁水或dDAVP治疗部分逆转，这与锂诱导的尿浓缩缺陷恢复缓慢的临床观察结果一致。
