Stanton B A
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, USA.
Wien Klin Wochenschr. 1997 Jun 27;109(12-13):457-64.
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is expressed in all nephron segments. Although mutations in CFTR are not associated with major changes in renal function, drug excretion by the kidneys is altered in cystic fibrosis (CF) as is the ability of the kidneys to concentrate and dilute the urine and excrete a salt load. It is not clear if these changes in renal function are secondary to decreased extracellular fluid volume caused by excessive losses of NaCl in sweat and feces or if they are related to primary defects in renal function caused by mutations in CFTR. Considerable evidence supports a role for CFTR in mediating Cl- secretion by the distal tubule, principal cells in the cortical collecting duct (CCD) and the inner medullary collecting duct (IMCD). In addition, CFTR is responsible for Cl- secretion into the lumen of cysts in polycystic kidneys and, therefore, contributes to cyst enlargement. Under some conditions--when Na+ absorption across the apical membrane of principal cells in the CCD is stimulated and the apical membrane potential is depolarized--the electrochemical gradient for Cl- will support Cl- absorption via CFTR Cl- channels. In addition to its function as a 3',5'-cAMP-activated Cl- channel, CFTR may play a role in intracellular vesicle acidification, protein processing, protein trafficking, secretion of ATP and the regulation of the epithelial Na channel (ENaC) and the secretory K+ channel (ROMK2) which mediate Na+ and K+ transport, respectively, across the CCD. Thus, CFTR may regulate Na+ and K+ excretion by the kidneys. The most common mutation in CFTR is delta F508, a mutation which causes improper folding of CFTR such that it is retained within the endoplasmic reticulum where it is degraded. Thus, in the majority of cases, CF is a trafficking disease. However, nothing is known about the intracellular trafficking of CFTR in the kidney. In preliminary studies we have developed a living cell model to study the intracellular trafficking of CFTR and delta F508-CFTR in renal epithelial cells in real time. Our ultimate goal is to elucidate the intracellular trafficking of CFTR and to identify therapeutic approaches to restore normal function to renal cells in CF and to block CFTR-mediated Cl- secretion in cysts in polycystic kidneys.
囊性纤维化跨膜传导调节因子（CFTR）氯离子通道在所有肾单位节段均有表达。尽管CFTR突变与肾功能的主要变化无关，但在囊性纤维化（CF）中，肾脏的药物排泄会发生改变，肾脏浓缩和稀释尿液以及排泄盐分的能力也会改变。目前尚不清楚这些肾功能变化是继发于汗液和粪便中NaCl过度流失导致的细胞外液量减少，还是与CFTR突变引起的肾功能原发性缺陷有关。大量证据支持CFTR在介导远端小管、皮质集合管（CCD）主细胞和髓质内集合管（IMCD）的氯离子分泌中发挥作用。此外，CFTR负责将氯离子分泌到多囊肾囊肿的管腔中，因此会导致囊肿增大。在某些情况下——当刺激CCD主细胞顶膜对钠离子的吸收且顶膜电位去极化时——氯离子的电化学梯度将支持通过CFTR氯离子通道进行氯离子吸收。除了作为一种3'，5'-环磷酸腺苷激活的氯离子通道发挥作用外，CFTR可能在细胞内囊泡酸化、蛋白质加工、蛋白质运输、ATP分泌以及上皮钠通道（ENaC）和分泌性钾通道（ROMK2）的调节中发挥作用，这两种通道分别介导钠离子和钾离子跨CCD的转运。因此，CFTR可能调节肾脏对钠离子和钾离子的排泄。CFTR最常见的突变是ΔF508，该突变导致CFTR折叠不当，使其滞留在内质网中并在那里降解。因此，在大多数情况下，CF是一种转运疾病。然而，关于CFTR在肾脏中的细胞内转运情况尚无了解。在初步研究中，我们建立了一个活细胞模型，以实时研究CFTR和ΔF508-CFTR在肾上皮细胞中的细胞内转运。我们的最终目标是阐明CFTR的细胞内转运过程，并确定恢复CF患者肾细胞正常功能以及阻断多囊肾囊肿中CFTR介导的氯离子分泌的治疗方法。
