Kwon T H, Laursen U H, Marples D, Maunsbach A B, Knepper M A, Frokiaer J, Nielsen S
Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C, United Kingdom.
Am J Physiol Renal Physiol. 2000 Sep;279(3):F552-64. doi: 10.1152/ajprenal.2000.279.3.F552.
Lithium (Li) treatment is often associated with nephrogenic diabetes insipidus (NDI). The changes in whole kidney expression of aquaporin-1 (AQP1), -2, and -3 as well as Na-K-ATPase, type 3 Na/H exchanger (NHE3), type 2 Na-Pi cotransporter (NaPi-2), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), and thiazide-sensitive Na-Cl cotransporter (TSC) were examined in rats treated with Li orally for 4 wk: protocol 1, high doses of Li (high Na(+) intake), and protocol 2, low doses of Li (identical food and normal Na(+) intake in Li-treated and control rats). Both protocols resulted in severe polyuria. Semiquantitative immunoblotting revealed that whole kidney abundance of AQP2 was dramatically reduced to 6% (protocol 1) and 27% (protocol 2) of control levels. In contrast, the abundance of AQP1 was not decreased. Immunoelectron microscopy confirmed the dramatic downregulation of AQP2 and AQP3, whereas AQP4 labeling was not reduced. Li-treated rats had a marked increase in urinary Na(+) excretion in both protocols. However, the expression of several major Na(+) transporters in the proximal tubule, loop of Henle, and distal convoluted tubule was unchanged in protocol 2, whereas in protocol 1 significantly increased NHE3 and BSC-1 expression or reduced NaPi-2 expression was associated with chronic Li treatment. In conclusion, severe downregulation of AQP2 and AQP3 appears to be important for the development of Li-induced polyuria. In contrast, the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na(+) transporters do not participate in the development of Li-induced polyuria.
锂（Li）治疗常与肾性尿崩症（NDI）相关。对口服锂4周的大鼠的全肾水通道蛋白-1（AQP1）、-2和-3以及钠钾ATP酶、3型钠氢交换体（NHE3）、2型钠磷共转运体（NaPi-2）、1型布美他尼敏感钠钾2氯共转运体（BSC-1）和噻嗪敏感钠氯共转运体（TSC）的表达变化进行了检测：方案1，高剂量锂（高钠摄入），方案2，低剂量锂（锂处理组和对照组大鼠食物相同且钠摄入正常）。两种方案均导致严重多尿。半定量免疫印迹显示，全肾AQP2丰度显著降低至对照组水平的6%（方案1）和27%（方案2）。相比之下，AQP1丰度未降低。免疫电子显微镜证实AQP2和AQP3显著下调，而AQP4标记未减少。两种方案中锂处理的大鼠尿钠排泄均显著增加。然而，方案2中近端小管、髓袢和远曲小管中几种主要钠转运体的表达未改变，而在方案1中，慢性锂处理与NHE3和BSC-1表达显著增加或NaPi-2表达降低有关。总之，AQP2和AQP3的严重下调似乎对锂诱导的多尿的发生很重要。相比之下，NHE3、BSC-1、钠钾ATP酶和TSC表达的增加或不变表明这些钠转运体不参与锂诱导的多尿的发生。
