Lee David B N, Huang Edmund, Ward Harry J
Division of Nephrology, Veterans Affairs Greater Los Angeles Healthcare System, California, USA.
Am J Physiol Renal Physiol. 2006 Jan;290(1):F20-34. doi: 10.1152/ajprenal.00052.2005.
The epithelial tight junction (TJ) has three major functions. As a "gate," it serves as a regulatory barrier separating and maintaining biological fluid compartments of different composition. As a "fence," it generates and maintains the apicobasal polarity of cells that form the confluent epithelium. Finally, the TJ proteins form a trafficking and signaling platform that regulates cell growth, proliferation, differentiation, and dedifferentiation. Six examples are selected that illustrate the emerging link between TJ dysfunction and kidney disease. First, the glomerular slit diaphragm (GSD) is evolved, in part, from the TJ and, on maturation, exhibits all three functions of the TJ. GSD dysfunction leads to proteinuria and, in some instances, podocyte dedifferentiation and proliferation. Second, accumulating evidence supports epithelial-mesenchymal transformation (EMT) as a major player in renal fibrosis, the final common pathway that leads to end-stage renal failure. EMT is characterized by a loss of cell-cell contact and apicobasal polarity, which are hallmarks of TJ dysfunction. Third, in autosomal dominant polycystic kidney disease, mutations of the polycystins may disrupt their known interactions with the apical junction complex, of which the TJ is a major component. This can lead to disturbances in epithelial polarity regulation with consequent abnormal tubulogenesis and cyst formation. Fourth, evidence for epithelial barrier and polarity dysregulation in the pathogenesis of ischemic acute renal failure will be summarized. Fifth, the association between mutations of paracellin-1, the first TJ channel identified, and clinical disorders of magnesium and calcium wasting and bovine renal fibrosis will be used to highlight an integral TJ protein that can serve multiple TJ functions. Finally, the role of WNK4 protein kinase in shunting chloride across the TJ of the distal nephron will be addressed.
上皮紧密连接(TJ)具有三大主要功能。作为一道“闸门”,它充当调节性屏障,分隔并维持不同成分的生物流体隔室。作为一道“围栏”,它产生并维持构成融合上皮的细胞的顶-基极性。最后,TJ蛋白形成一个转运和信号平台,调节细胞生长、增殖、分化和去分化。选取了六个例子来说明TJ功能障碍与肾脏疾病之间新出现的联系。第一,肾小球裂孔隔膜(GSD)部分由TJ演化而来,成熟时展现出TJ的所有三大功能。GSD功能障碍导致蛋白尿,在某些情况下还会导致足细胞去分化和增殖。第二,越来越多的证据支持上皮-间质转化(EMT)是肾纤维化的主要参与者,肾纤维化是导致终末期肾衰竭的最终共同途径。EMT的特征是细胞间接触和顶-基极性丧失,而这是TJ功能障碍的标志。第三,在常染色体显性多囊肾病中,多囊蛋白的突变可能会破坏它们与顶端连接复合体已知的相互作用,而TJ是该复合体的主要组成部分。这可能导致上皮极性调节紊乱,进而导致异常的肾小管形成和囊肿形成。第四,将总结缺血性急性肾衰竭发病机制中上皮屏障和极性失调的证据。第五,首个被鉴定的TJ通道——紧密连接蛋白-1的突变与镁和钙流失的临床病症以及牛肾纤维化之间的关联,将被用于突出一种能发挥多种TJ功能的完整TJ蛋白。最后,将探讨WNK4蛋白激酶在氯离子跨远端肾单位TJ分流中的作用。