Targeted CFTR gene disruption with zinc-finger nucleases in human intestinal epithelial cells induces oxidative stress and inflammation

Kleme, Marie-Laure; Sané, Alain Théophile; Garofalo, Carole; Lévy, Émile

doi:10.1016/j.biocel.2016.02.022

Cited by 16 publications

(35 citation statements)

References 77 publications

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“…Moreover, mutation of CFTR or loss of function of CFTR has also been shown to directly affect the intracellular redox status in CF lungs (26,27). Additionally, in CF mouse intestines or CFTR-knockdown intestinal epithelial cells, there is an upregulation of genes involved in oxidative stress and inflammation (19,28). These findings collectively suggest that oxidative stress and inflammation are implicated in the pathophysiology of several disorders in CF subjects.…”

Section: Discussionmentioning

confidence: 95%

“…To further investigate the mechanism of CFTR with regard to protecting endothelial function, the involvement of NF-κB signaling in damage responses triggered by high glucose in endothelial cells was first investigated, as various studies have indicated the intrinsic activation of this signaling in CF (19,29). Moreover, NF-κB has been found to be an essential regulator of various genes, including inflammatory biomediators ICAM-1, VCAM-1, E-selectin and IL-1β (19,30). Once activated, the p65 subunit of NF-κB is released and translocates into the nucleus to regulate the target genes (31).…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis. Western blot analysis was performed as previously described (19). HUVECs were washed with phosphate-buffered saline (PBS) and harvested in mammalian protein extraction reagent (Thermo Fisher Scientific, Inc.) containing 1 mM protease inhibitor (Roche Diagnostics, Laval, QC, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…CFTR loss or aberration in the lungs leads to bacterial infection in association with inflammation as a consequence of abnormal reabsorption of sodium and water, and impairment of mucociliary clearance (18). Even if multiple studies have suggested that defective or dysfunctional CFTR can also result in bacterial colonization, inflammation usually occurs in the earliest stage of lung damage prior to bacterial infection in CF patients (19,20), indicating the direct role of CFTR in the inflammatory process. Moreover, NF-κB and MAPK signaling pathways have been suggested to be implicated in the regulation of the inflammatory response of CF airway epithelia (16,19,21).…”

Section: Introductionmentioning

confidence: 99%

“…Even if multiple studies have suggested that defective or dysfunctional CFTR can also result in bacterial colonization, inflammation usually occurs in the earliest stage of lung damage prior to bacterial infection in CF patients (19,20), indicating the direct role of CFTR in the inflammatory process. Moreover, NF-κB and MAPK signaling pathways have been suggested to be implicated in the regulation of the inflammatory response of CF airway epithelia (16,19,21). Although these findings have provided evidence that CFTR defects are likely to contribute to inflammation, little attention has been devoted to the investigation of the role of CFTR in hyperglycemia-induced vascular endothelial cell inflammation.…”

Section: Introductionmentioning

confidence: 99%

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CFTR ameliorates high glucose-induced oxidative stress and inflammation by mediating the NF-κB and MAPK signaling pathways in endothelial cells

et al. 2018

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Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive production of oxidative stress and pro-inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regulator (CFTR). However, little information is available about the role of CFTR in hyperglycemia‑induced endothelial cell oxidative stress and inflammation. In the present study, a high glucose‑treatment was applied in human umbilical vein endothelial cells with CFTR overexpression or inhibition, and the oxidative and inflammatory characteristics were measured. It was shown that CFTR protein and mRNA expression were reduced by glucose in a concentration‑dependent manner. Overexpression of CFRT via adenoviral infection significantly inhibited the production of reactive oxygen species and inflammatory biomediators induced by high glucose. Conversely, pharmacological inhibition of CFTR led to the opposite effects. Mechanistically, nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinase (MAPK) signaling were activated following high glucose treatment, which were inhibited by CFTR overexpression and enhanced by CFTR inhibition. The pro‑inflammatory effect of CFTR inhibition was abolished by pharmacological inhibition of the NF‑κB or MAPK pathways. Moreover, inhibition of MAPK abrogated CFTR inhibition‑induced NF‑κB nuclear translocation, whereas NF‑κB inhibitor produced no effects on MAPK activation. Additionally, antioxidant treatment inhibited the high glucose‑induced decrease in CFTR expression and the increase in inflammatory responses. Collectively, these findings revealed that CFTR attenuates high glucose‑induced endothelial cell oxidative stress and inflammation through inactivation of NF‑κB and MAPK signaling, indicating that elevation of CFRT expression may be a novel strategy in preventing endothelial dysfunction in diabetes.

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