Investigation of pancreatic ductal fluid and HCO3-secretion in NHERF1 knockout and wild-type mice

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Background: Na+/H+ exchanger regulatory factor-1 (NHERF-1) is a scaffolding protein which is responsible for the apical localization of cystic fibrosis transmembrane conductance regulator (CFTR), a key player in pancreatic ductal bicarbonate secretion. The aim of this study was to evaluate the role of NHERF-1 in pancreatic ductal localization of CFTR, and in bicarbonate and fluid secretion. Methods: The expression of CFTR was analysed by immunohistochemistry. Pancreatic juice was collected from anesthetized wild-type (WT) and NHERF-1 knock-out (KO) mice in basal and secretin-stimulated conditions. We isolated intra/interlobular ducts from the pancreas of NHERF-1 WT and KO mice. Fluid secretion into the closed luminal space of the ducts was analysed using a swelling technique. Luminal anion exchange activity was determined by microfluorometry. Results: Pancreatic ductal CFTR staining was more diffuse and less apical in the NHERF-1 KO vs. WT mice. The volume of pancreatic juice was significantly reduced in NHERF-1 KO vs. WT mice under both basal and secretin-stimulated conditions in vivo. Accordingly, the forskolin-stimulated fluid secretory rate was significantly lower in ducts from KO vs. WT mice in standard HCO3-/CO2 solution in vitro. The reduction of ductal bicarbonate secretion in the NHERF-1 KO mice was confirmed by the alkali load and the inhibitor stop methods on basolaterally perfused ducts and by the luminal Cl- removal technique on microperfused ducts. Conclusion: Our results suggest that pancreatic ductal NHERF-1 is involved in CFTR localization and is essential for fluid and bicarbonate secretion. This study was supported by OTKA, MTA/DFG and NFÜ/TÁMOP.

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