Kortenoeven Marleen L A, Li Yuedan, Shaw Stephen, Gaeggeler Hans-Peter, Rossier Bernard C, Wetzels Jack F M, Deen Peter M T
Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Kidney Int. 2009 Jul;76(1):44-53. doi: 10.1038/ki.2009.91. Epub 2009 Apr 15.
Lithium therapy frequently induces nephrogenic diabetes insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site for lithium and the beneficial effect of amiloride may be through inhibiting lithium entry. Using a mouse collecting duct cell line, we found that vasopressin caused an increase in Aquaporin 2 (AQP2) expression which was reduced by clinically relevant lithium concentrations similar to what is seen with in vivo models of this disease. Further amiloride or benzamil administration prevented this lithium-induced downregulation of AQP2. Amiloride reduced transcellular lithium transport, intracellular lithium concentration, and lithium-induced inactivation of glycogen synthase kinase 3beta. Treatment of rats with lithium downregulated AQP2 expression, reduced the principal-to-intercalated cell ratio, and caused polyuria, while simultaneous administration of amiloride attenuated all these changes. These results show that ENaC is the major entry site for lithium in principal cells both in vitro and in vivo. Blocking lithium entry with amiloride attenuates lithium-induced diabetes insipidus, thus providing a rationale for its use in treating this disorder.
锂盐治疗常诱发肾性尿崩症；氨氯吡咪在一些临床病例中似乎可预防其发生。氨氯吡咪可阻断位于主细胞顶端膜的上皮钠通道（ENaC）；因此一种可能性是，ENaC是锂进入细胞的主要途径，氨氯吡咪的有益作用可能是通过抑制锂的进入。利用小鼠集合管细胞系，我们发现血管加压素可使水通道蛋白2（AQP2）表达增加，而临床相关锂浓度可使其降低，这与该疾病的体内模型所见情况相似。此外，给予氨氯吡咪或苄甲氯可防止这种锂诱导的AQP2下调。氨氯吡咪可减少跨细胞锂转运、细胞内锂浓度以及锂诱导的糖原合酶激酶3β失活。用锂盐处理大鼠可下调AQP2表达，降低主细胞与闰细胞的比例，并导致多尿，而同时给予氨氯吡咪可减轻所有这些变化。这些结果表明，ENaC是体外和体内主细胞中锂进入的主要途径。用氨氯吡咪阻断锂的进入可减轻锂诱导的尿崩症，从而为其用于治疗该疾病提供了理论依据。
