Targeting cGMP pathway with vardenafil to correct F508del-CFTR function and localization in the gastrointestinal tract
(2013) 2013 ECFS Basic Sciences Conference — Location: Malaga, Spain (20.March.2013)
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- Vardenafil, a cGMP-dependent phosphodiesterase type 5 inhibitor, normalizes defective CFTR-mediated chloride secretion across the nasal mucosa of mice homozygous for the F508del mutation (CF). This work aimed at 1) studying the potential of¬ vardenafil to rescue CFTR function across the rectal mucosa, representative of the gastrointestinal (G¬I) tract; 2) validating immunohistostaining assays to quantify CFTR expression in mouse colon tissue and to evaluate correction of mislocalized F508del-CFTR by treatment with vardenafil. CFTR function was assessed by quantifying potential difference across the rectal mucosa. Sodium hyperabsorption (40.2 ± 4.0 mV vs 20 ± 1.8 mV; p< 0.001; mean ± SEM) and reduced chloride transport (-4.2 ± 0.5 mV vs -9.4 ± 0.9 mV; p=0.002) were typically found in CF compared to wild-type (WT) mice. Vardenafil, applied as a single intraperitoneal dose (0.14 mg/kg) completely restored chloride transport (-9.3 ± 1.2 mV) in CF. Immunohistostaining studies showed reduced CFTR expression at cell membrane in CF mouse colon preparations: in untreated conditions, the ratio of CFTR-specific fluorescence (RF) of the cell membrane and that of the rest of the cell was lower in CF (1.4 ± 0.1) than in WT (1.9 ± 0.1; p < 0.001). The RF was increased in vardenafil-treated (2.2 ± 0.1) compared to untreated CF colon tissues (p <0.0001). Our findings pointed out the intestinal mucosa as a valuable target tissue to study CFTR function and localization and to evaluate efficacy of therapeutic strategies in CF. Vardenafil restores ion transport abnormalities across the GI epithelium acting as a corrector of the cell mislocalization of F508del-CFTR. This study provides compelling support for targeting cGMP signaling pathway in CF pharmacotherapy.
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Dhooghe, B., Noël, S., Bouzin, C., Lebecque, P., Wallemacq, P., & Leal, T. (2013). Targeting cGMP pathway with vardenafil to correct F508del-CFTR function and localization in the gastrointestinal tract. 2013 ECFS Basic Sciences Conference, Malaga, Spain. https://hdl.handle.net/2078.5/205592