Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl− channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.
Highlights
Kidney fibrosis is a common histological manifestation of functional decline in most cases of end-stage kidney diseases
Since hypoxia is a major mediator of EpithelialMesenchymal Transition (EMT) during kidney fibrosis[44], we investigated the influence of this pathophysiological important factor on the expression of CFTR in Madin-Darby canine kidney cell line Madin–Darby canine kidney (MDCK) and human tubular epithelial cell line HK-2, which are widely used as in vitro models to study EMT and renal dysfunction[45]
Cells by hypoxia (Full-length blot is shown in Supplementary Figure S7b.); (c) Real time-PCR assay showing decreased mRNA expression of CFTR induced by hypoxia in HK-2 cells,*p < 0.05; (d) Western blot showing decreased expression of CFTR induced by hypoxia in HK-2 cells (Full-length blot is shown in Supplementary Figure S7c.); (e) Western blot showing the expression changes of hypoxia-inducible factor-1α (HIF-1α) and EMT markers induced by hypoxia in MDCK cells, quantification analysis is shown in the lower panel, *p < 0.05; (Full-length blot is shown in Supplementary Figure S7d.) (f) Immunofluorescent staining showing dramatically increased HIF-1α and reduced CFTR protein levels in tubular epithelial cells at inner cortices in ureteric obstruction (UUO) kidney
Summary
Kidney fibrosis is a common histological manifestation of functional decline in most cases of end-stage kidney diseases. Activation of β-catenin in tubular epithelial cells induces EMT, as well as the expression of several fibrosis-related genes in vitro[22,23,24] These results suggest that activation of tubular β-catenin probably plays a critical role in the pathogenesis and progression of kidney fibrosis[16]. Permanent microalbuminuria occurs in more than 6% of patients with cystic fibrosis[30] Despite all these link, the exact role of CFTR in the pathogenesis of chronic kidney diseases has never been investigated. TGF-β and hypoxia inducing factor α (HIFα), key inducers of kidney fibrosis, have been demonstrated to suppress the expression and/or localization of CFTR in the context of epithelial cells[37,38,39] Based on these observations, we hypothesized that dysregulation of CFTR might lead to aberrant activation of Wnt/β-catenin pathway and development of kidney fibrosis. We undertook the present study to investigate this possibility using kidney epithelial cell lines, UUO mouse model and CFTR mutant mice in conjunction with genetic manipulation in vitro and in vivo
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