Jouret François, Bernard Alfred, Hermans Cédric, Dom Geneviève, Terryn Sara, Leal Teresinha, Lebecque Patrick, Cassiman Jean-Jacques, Scholte Bob J, de Jonge Hugo R, Courtoy Pierre J, Devuyst Olivier
Division of Nephrology, Université catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium.
J Am Soc Nephrol. 2007 Mar;18(3):707-18. doi: 10.1681/ASN.2006030269. Epub 2007 Feb 7.
Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. Cftr(-/-) mice showed impaired (125)I-beta(2)-microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in Cftr(DeltaF/DeltaF) mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR versus ClC-5 loss likely reflects functional heterogeneity along the PT.
氯离子通道囊性纤维化跨膜传导调节因子（CFTR）的失活会导致囊性纤维化（CF）。尽管CFTR在肾脏中表达，但CF患者中尚未有压倒性的肾脏表型记录。本研究调查了CFTR在肾脏中的表达、亚细胞分布和加工过程；使用各种小鼠模型评估CFTR在近端小管（PT）内吞作用中的作用；并测试了这些发现在CF患者中的相关性。小鼠肾脏中CFTR mRNA的水平接近在肺中发现的水平。CFTR位于PT细胞的顶端区域，在PT的直部（S3）强度最大。分级分离显示CFTR与氯离子/质子交换体ClC-5在PT内体中共分布。Cftr(-/-)小鼠显示（125）I-β2-微球蛋白摄取受损，同时S3段中多配体受体cubilin的量减少，并且cubilin及其低分子量（LMW）配体大量丢失到尿液中。在Cftr(DeltaF/DeltaF)小鼠中，受体介导的内吞作用缺陷不太一致，其特征是表型异质性大，与缺乏ClC-5的小鼠相比程度中等。在一组CF患者中也记录到了显著的LMW蛋白尿（尤其是转铁蛋白尿），但哮喘和慢性肺部炎症患者中未出现。总之，CFTR失活导致受体介导的PT内吞作用出现中度缺陷，与小鼠和人类中的cubilin缺陷和显著的LMW蛋白尿有关。CFTR缺失与ClC-5缺失导致的内吞作用缺陷程度可能反映了PT沿程的功能异质性。
