CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis
CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis
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DOI：
10.1152/ajpgi.1999.277.3.g709
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发表时间：
1999-09-01
影响因子：
4.5
通讯作者：
Kunzelmann, K
中科院分区：
文献类型：
--
作者：
Mall, M;Bleich, M;Kunzelmann, K
囊性纤维化(CF)患者表现出特征性的上皮离子转运缺陷，如cAMP依赖的氯-分泌失败。由于囊性纤维化跨膜电导调节器(CFTR)也是上皮性钠离子通道(ENaC)的下调子，因此在CF患者的呼吸道中发现Na+电导增强。在这里，我们检查了CF患者的结肠上皮是否也存在上皮钠离子电导增强，并探讨了其潜在的机制。因此，通过一种新型的Ussing小室测量了跨上皮电压，并确定了等效短路电流(ISC-eq)。非CF组织表现出cAMP依赖的Cl-分泌，而CF患者的活检组织中没有这种分泌。相应地，当内源性前列腺素的合成被吲哚美辛阻断时，ISC-eq在非CF上皮细胞中被抑制，但在CF上皮细胞中不受抑制。在吲哚美辛存在的情况下，在CF组织中检测到较大比例的对阿米洛利敏感的ISC-ES，这表明CF患者结肠粘膜的ENaC电导增强。Forskolin和IBMX增加细胞内cAMP可抑制非CF组织中对阿米洛利敏感的ENaC电流，但在CF活检组织中无此作用。因此，上皮细胞Na+电导增强存在于CF结肠中，可能是由于CFTR缺失下调所致。
Cystic fibrosis (CF) patients show characteristic defects in epithelial ion transport, such as failure in cAMP-dependent Cl- secretion. Because the cystic fibrosis transmembrane conductance regulator (CFTR) also functions as a downregulator of epithelial Na+ channels (ENaC), enhanced Na+ conductance was found in the airways of CF patients. Here, we examined whether enhanced epithelial Na+ conductance is also present in the colonic epithelium of CF patients and examined the underlying mechanisms. Thus transepithelial voltages were measured, and equivalent short-circuit currents (Isc-eq) were determined by means of a novel type of Ussing chamber. Non-CF tissues demonstrated cAMP-dependent Cl- secretion that was absent in biopsies of CF patients. Correspondingly, Isc-eq was inhibited in non-CF but not in CF epithelia when synthesis of endogenous prostaglandins was blocked by indomethacin. Ln the presence of indomethacin, a larger portion of amiloride-sensitive Isc-es was detected in CF tissues, suggesting enhanced ENaC conductance in colonic mucose of CF patients. Increase of intracellular cAMP by forskolin and IBMX inhibited amiloride-sensitive ENaC currents in non-CF tissues but not in CF biopsies. Therefore, enhanced epithelial Na+ conductance is present in the CF colon and is probably due to missing downregulation by CFTR.