Thiopurines impair the apical plasma membrane expression of CFTR in pancreatic ductal cells via RAC1 inhibition
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Published:2023-01
Issue:1
Volume:80
Page:
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ISSN:1420-682X
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Container-title:Cellular and Molecular Life Sciences
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language:en
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Short-container-title:Cell. Mol. Life Sci.
Author:
Tél Bálint, Papp Noémi, Varga Árpád, Szabó Viktória, Görög Marietta, Susánszki Petra, Crul Tim, Kis Aletta, Sendstad Ingrid H., Bagyánszki Mária, Bódi Nikolett, Hegyi Péter, Maléth JózsefORCID, Pallagi PetraORCID
Abstract
Abstract
Background and aims
Thiopurine-induced acute pancreatitis (TIP) is one of the most common adverse events among inflammatory bowel disease patients treated with azathioprine (AZA), representing a significant clinical burden. Previous studies focused on immune-mediated processes, however, the exact pathomechanism of TIP is essentially unclear.
Methods
To model TIP in vivo, we triggered cerulein-induced experimental pancreatitis in mice receiving a daily oral dose of 1.5 mg/kg AZA. Also, freshly isolated mouse pancreatic cells were exposed to AZA ex vivo, and acinar cell viability, ductal and acinar Ca2+ signaling, ductal Cl– and HCO3– secretion, as well as cystic fibrosis transmembrane conductance regulator (CFTR) expression were assessed using microscopy techniques. Ras-related C3 botulinum toxin substrate (RAC1) activity was measured with a G-LISA assay. Super-resolution microscopy was used to determine protein colocalization.
Results
We demonstrated that AZA treatment increases tissue damage in the early phase of cerulein-induced pancreatitis in vivo. Also, both per os and ex vivo AZA exposure impaired pancreatic fluid and ductal HCO3– and Cl– secretion, but did not affect acinar cells. Furthermore, ex vivo AZA exposure also inhibited RAC1 activity in ductal cells leading to decreased co-localization of CFTR and the anchor protein ezrin, resulting in impaired plasma membrane localization of CFTR.
Conclusions
AZA impaired the ductal HCO3– and Cl– secretion through the inhibition of RAC1 activity leading to diminished ezrin-CFTR interaction and disturbed apical plasma membrane expression of CFTR. We report a novel direct toxic effect of AZA on pancreatic ductal cells and suggest that the restoration of ductal function might help to prevent TIP in the future.
Funder
Hungarian Ministry of Human Capacities Hungarian National Research, Development and Innovation Office Magyar Tudományos Akadémia Hungarian National Excellence Programme Emberi Eroforrások Minisztériuma Albert Szent-Györgyi Research Grant Hungarian National Talent Programme University of Szeged
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Cellular and Molecular Neuroscience,Pharmacology,Molecular Biology,Molecular Medicine
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