Tingskov Stine Julie, Kwon Tae-Hwan, Frøkiær Jørgen, Nørregaard Rikke
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, South Korea.
Front Physiol. 2018 Jul 12;9:903. doi: 10.3389/fphys.2018.00903. eCollection 2018.
Lithium is widely used in the treatment of bipolar affective disorders, but often causes nephrogenic diabetes insipidus (NDI), a condition characterized by a severe urinary concentrating defect. Lithium-induced NDI is associated with dysregulation of the amiloride-sensitive epithelial sodium channel (ENaC), which is essential for renal sodium reabsorption. Sex hormones have been shown to affect the expression of aquaporin-2 (AQP2) and sodium transporters. Therefore, we evaluated whether tamoxifen (TAM), a selective estrogen receptor modulator (SERM), would affect lithium-induced dysregulation of ENaC subunits and natriuresis. Rats were fed with lithium-containing food for 2 weeks to induce NDI and natriuresis. TAM was administered daily via gastric gavage after 1 week of lithium administration. Lithium treatment alone resulted in increased urinary sodium excretion and significant reduction of βENaC and γENaC at both RNA and protein levels. In addition, the plasma sodium level reduced after lithium treatment. Administration of TAM prevented increased urinary sodium excretion as well as attenuated the downregulation of βENaC and γENaC. Consistent with these findings, immunohistochemistry (IHC) showed stronger labeling of βENaC and γENaC subunits in the apical domain of the collecting duct cells in the cortical tissue of lithium-fed rats treated with TAM. Other major sodium transporters including NaPi-2, NKCC2, Na/K-ATPase, and NHE3, are believed not to have an effect on the increased urinary sodium excretion since their expression increased or was unchanged after treatment with lithium. In conclusion, the results demonstrated that TAM rescued the adverse effects of the lithium-induced increase in fractional excretion of sodium after the establishment of lithium-induced NDI.
锂广泛用于治疗双相情感障碍，但常导致肾性尿崩症（NDI），这是一种以严重的尿液浓缩功能缺陷为特征的病症。锂诱导的NDI与氨氯地平敏感的上皮钠通道（ENaC）失调有关，ENaC对肾脏钠重吸收至关重要。已表明性激素会影响水通道蛋白2（AQP2）和钠转运蛋白的表达。因此，我们评估了选择性雌激素受体调节剂（SERM）他莫昔芬（TAM）是否会影响锂诱导的ENaC亚基失调和利钠作用。给大鼠喂食含锂食物2周以诱导NDI和利钠作用。在给予锂1周后，每天通过胃管给予TAM。单独锂治疗导致尿钠排泄增加，且βENaC和γENaC在RNA和蛋白质水平均显著降低。此外，锂治疗后血浆钠水平降低。给予TAM可防止尿钠排泄增加，并减弱βENaC和γENaC的下调。与这些发现一致，免疫组织化学（IHC）显示，在用TAM治疗的喂食锂的大鼠皮质组织中，集合管细胞顶端区域的βENaC和γENaC亚基标记更强。其他主要的钠转运蛋白，包括NaPi-2、NKCC2、Na/K-ATP酶和NHE3，被认为对尿钠排泄增加没有影响，因为在用锂治疗后它们的表达增加或未改变。总之，结果表明，在锂诱导的NDI建立后，TAM挽救了锂诱导的钠排泄分数增加的不良影响。
