The basolateral potassium channel KCNJ10 (Kir4.1), is expressed in the renal distal convoluted tubule and controls the activity of the thiazide-sensitive sodium chloride cotransporter. Loss-of-function mutations of KCNJ10 cause EAST/SeSAME syndrome with salt wasting and severe hypokalemia. KCNJ10 is also expressed in the principal cells of the collecting system. However, its pathophysiological role in this segment has not been studied in detail. To address this, we generated the mouse model AQP2cre:Kcnj10flox/flox with a deletion of Kcnj10 specifically in the collecting system (collecting system-Kcnj10-knockout). Collecting system-Kcnj10-knockout mice responded normally to standard and high potassium diet. However, this knockout exhibited a higher kaliuresis and lower plasma potassium than control mice when treated with thiazide diuretics. Likewise, collecting systemKcnj10-knockout displayed an inadequately high kaliuresis and renal sodium retention upon dietary potassium restriction. In this condition, these knockout mice became hypokalemic due to insufficient downregulation of the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK) in the collecting system. Consistently, the phenotype of collecting system-Kcnj10-knockout was fully abrogated by ENaC inhibition with amiloride and ameliorated by genetic inactivation of ROMK in the collecting system. Thus, KCNJ10 in the collecting system contributes to the renal control of potassium homeostasis by regulating ENaC and ROMK. Hence, impaired KCNJ10 function in the collecting system predisposes for thiazide and low potassium diet-induced hypokalemia and likely contributes to the pathophysiology of renal potassium loss in EAST/SeSAME syndrome.

中文翻译：

---

收集系统特定的Kcnj10缺失是噻嗪和低钾饮食引起的低钾血症的诱因。

基底外侧钾通道KCNJ10（Kir4.1）在肾脏远端的曲折小管中表达，并控制噻嗪类敏感性氯化钠共转运蛋白的活性。KCNJ10的功能丧失突变导致EAST / SeSAME综合征，伴有盐消耗和严重的低钾血症。KCNJ10也表达在收集系统的主要细胞中。但是，尚未详细研究其在这一节段中的病理生理作用。为了解决这个问题，我们生成了鼠标模型AQP2cre：Kcnj10flox / flox，其中删除了Kcnj10，特别是在收集系统中（收集系统-Kcnj10-knockout）。收集系统-Kcnj10-敲除小鼠对标准和高钾饮食正常反应。但是，当用噻嗪类利尿剂治疗时，与对照组相比，这种基因敲除表现出更高的利尿作用和更低的血浆钾含量。同样，收集系统Kcnj10的敲除显示出在饮食中限制钾的作用下钾尿不足和肾钠sodium留不足。在这种情况下，由于收集系统中上皮钠通道（ENaC）和肾外髓质钾通道（ROMK）的下调不足，这些基因敲除小鼠变为低钾血症。一致地，通过阿米洛利的ENaC抑制作用完全消除了收集系统-Kcnj10-敲除的表型，并且通过收集系统中ROMK的基因失活改善了该表型。因此，收集系统中的KCNJ10通过调节ENaC和ROMK有助于肾脏对钾稳态的控制。因此，