肾小管管周膜Kir4.1及Kir4.1/Kir5.1通道的功能及调控

The function and regulation of basolateral Kir4.1 and Kir4.1/Kir5.1 in renal tubules

远端肾小管管周膜内向整流钾通道(inwardly-rectifying potassium channel, Kir)可控制细胞膜静息电位和跨膜电压,从而参与水和电解质转运的调控。Kir4.1及Kir4.1/Kir5.1异源四聚体高表达于髓袢升支粗段、远曲小管、连接小管和集合管管周膜,是调控Na^+重吸收和K^+分泌的重要转运蛋白。编码Kir4.1的KCNJ10功能缺失性突变可导致EAST/SeSAME综合征的发生,主要表现为:癫痫、共济失调、神经性耳聋及以盐丢失、低镁血症、低钾血症和代谢性碱中毒为主要表现的水盐代谢紊乱。而靶向敲除KCNJ16编码的Kir5.1除了引起低血钾以外,还表现为严重的高氯性代谢性酸中毒和高钙尿。另外,KCNJ10敲除抑制钠氯同向转运体在远曲小管管腔膜的表达及活动,同时,可增强连接小管和集合管上皮钠通道的表达。细胞内的pH值、多巴胺、胰岛素和胰岛素样生长因子等因素均可调控Kir4.1和Kir4.1/Kir5.1通道活动,涉及的机制包括PKC、PI3K、Src家族以及WNK-SPAK等信号转导途径。本综述对近年肾小管管周膜Kir的研究进展加以总结,重点阐述Kir4.1和Kir4.1/Kir5.1通道功能及其活性调控。

Basolateral inwardly-rectifying K+ channels (Kir) play an important role in the control of resting membrane potential and transepithelial voltage, thereby modulating water and electrolyte transport in the distal part of nephron. Kir4.1 and Kir4.1/Kir5.1 heterotetramer are abundantly expressed in the basolateral membrane of late thick ascending limb (TAL), distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD). Loss-of-function mutations in KCNJ10 cause EAST/SeSAME syndrome in humans associated with epilepsy, ataxia, sensorineural deafness and water-electrolyte metabolism imbalance, which is characterized by salt wasting, hypomagnesaemia, hypokalaemia and metabolic alkalosis. In contrast, mice lacking Kir5.1 have severe renal phenotype apart from hypokalaemia such as high chlorine metabolic acidosis and hypercalcinuria. The genetic knockout or functional inhibition of Kir4.1 suppresses Na-Cl cotransporter (NCC) expression and activity in the DCT. However, the downregulation of Kir4.1 increases epithelial Na+ channel (ENaC) expression in the collecting duct. Recently, factors regulating expression and activity of Kir4.1 and Kir4.1/Kir5.1 were identified, such as cell acidification, dopamine, insulin and insulin-like growth factor-1. The involved mechanisms include PKC, PI3K, Src family protein tyrosine kinases and WNK-SPAK signal transduction pathways. Here we review the progress of renal tubule basolateral Kir, and mainly discuss the function and regulation of Kir4.1 and Kir4.1/Kir5.1.