Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis

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 EpithelialMesenchymal 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.Kidney fibrosis is a common histological manifestation of functional decline in most cases of end-stage kidney diseases. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation, leading to myofibroblast activation and an accumulation of extracellular matrix (ECM) [1][2][3] . While the cellular origin of myofibroblasts remains to be a subject of intensive debate, numerous animal and clinical studies have pointed to epithelial-to-mesenchymal-transition (EMT) from the tubular epithelial cells as one of the major contributors leading to the generation of myofibroblasts and overproduction of interstitial ECM 4-9 . A multitude of biochemical signaling pathways has been proposed to be associated with the development of kidney fibrosis [10][11][12] . While Wnt/β-catenin signaling is functionally important in normal kidney development 13, 14 , aberrant activation of Wnt/β-catenin signaling and subsequent downstream targets, such as matrix metalloproteinases (MMPs), fibronectin and snail, has been observed in the progression of tubulointerstitial kidney fibrosis in unilateral ureteral obstruction (UUO) model [15][16][17] and different types of kidney diseases [18][19][20][21] . Of interest, β-catenin is predominantly up-regulated in renal tubular epithelium of the fibrotic kidneys, suggesting that tubular cells are the major targets of canonical Wnt signaling. In addition, 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...

The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression

“…[18][19][20] These results suggest that activation of b-catenin signaling probably plays a critical role in the pathogenesis and progression of kidney fibrosis. 21 Sirtuins (Sirts), mammalian Sir2 orthologs, are a highly conserved family of nicotinamide adenine dinucleotidedependent protein deacetylases, which have been found to be important regulators in the aging process, inflammation, cancer, and metabolic and neurodegenerative diseases. 22 To date, 7 Sirtuins (Sirt1 to Sirt7) have been identified in various subcellular localizations, which have different biological functions through regulating distinctive target proteins.…”

KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway

“…Although observed in previous studies, our data did not indicate alterations in the β-catenin signaling in the CF context. We speculate that this may be due to the fact that those studies used different cell models/organisms [ 36 , 38 , 39 , 40 ]. It is also possible that the levels of active β-catenin were altered because we only measured total β-catenin.…”

Role of ion channels in gastrointestinal cancer

“…This study analyzed Wnt/β-catenin signaling in total intestinal tissue rather than the crypt and so may reflect a different role for CFTR outside the stem cell compartment. Further, the effect of CFTR deficiency on Wnt/β-catenin activity varied by tissue in several other studies by this group[100]. In addition, Wnt/β-catenin signaling may also play different roles at different stages of CRC.…”