The Importance of Aquaporin 1 in Pancreatitis and Its Relation to the CFTR Cl- Channel.

Viktória Venglovecz,Katalin Borka,Zoltán Rakonczay,László G Puskás,Eszter Becskeházi,Eleonóra Gál,Péter Hegyi,Ágnes Zvara,Anita Balázs,Emese Tóth,Jens-Peter Kühn,Markus M Lerch,Lajos V Kemény,Matthias Sendler,Julia Mayerle,Zsolt Balla,Petra Pallagi

doi:10.3389/fphys.2018.00854

Abstract

Aquaporins (AQPs) facilitate the transepithelial water flow involved in epithelial fluid secretion in numerous tissues; however, their function in the pancreas is less characterized. Acute pancreatitis (AP) is a serious disorder in which specific treatment is still not possible. Accumulating evidence indicate that decreased pancreatic ductal fluid secretion plays an essential role in AP; therefore, the aim of this study was to investigate the physiological and pathophysiological role of AQPs in the pancreas. Expression and localization of AQPs were investigated by real-time PCR and immunocytochemistry, whereas osmotic transmembrane water permeability was estimated by the dye dilution technique, in Capan-1 cells. The presence of AQP1 and CFTR in the mice and human pancreas were investigated by immunohistochemistry. Pancreatic ductal HCO3- and fluid secretion were studied on pancreatic ducts isolated from wild-type (WT) and AQP1 knock out (KO) mice using microfluorometry and videomicroscopy, respectively. In vivo pancreatic fluid secretion was estimated by magnetic resonance imaging. AP was induced by intraperitoneal injection of cerulein and disease severity was assessed by measuring biochemical and histological parameters. In the mice, the presence of AQP1 was detected throughout the whole plasma membrane of the ductal cells and its expression highly depends on the presence of CFTR Cl- channel. In contrast, the expression of AQP1 is mainly localized to the apical membrane of ductal cells in the human pancreas. Bile acid treatment dose- and time-dependently decreased mRNA and protein expression of AQP1 and reduced expression of this channel was also demonstrated in patients suffering from acute and chronic pancreatitis. HCO3- and fluid secretion significantly decreased in AQP1 KO versus WT mice and the absence of AQP1 also worsened the severity of pancreatitis. Our results suggest that AQP1 plays an essential role in pancreatic ductal fluid and HCO3- secretion and decreased expression of the channel alters fluid secretion which probably contribute to increased susceptibility of the pancreas to inflammation.

Highlights

The pancreas secretes 1.5–2 l of fluid per day (Hegyi et al, 2011a; Pallagi et al, 2015)
Human tissues and transgenic mice, we have shown that AQP1 plays essential role in ductal fluid and HCO3− secretion, lack of CFTR decreases its expression and deletion of AQP1 is strongly associated with increased susceptibility of the gland to pancreatitis
We showed that the rate of acidification significantly reduced in AQP1 knock out (KO) (42 ± 3.2%) vs. WT ducts indicating that pancreatic ductal HCO3− secretion is impaired in the absence of AQP1 (Figures 2F,G)

Summary

Introduction

The pancreas secretes 1.5–2 l of fluid per day (Hegyi et al, 2011a; Pallagi et al, 2015). In the last few years, the importance of ion transport proteins has been highlighted in the course of pancreatitis; intensive research has been conducted in order to characterize their pathological roles (Hegyi and Rakonczay, 2015; Pallagi et al, 2015) These clinical and experimental studies indicate that impaired ductal HCO3− secretion makes the pancreas more susceptible to inflammatory diseases such as acute or chronic pancreatitis (CP) (Hegyi and Rakonczay, 2010; Hegyi et al, 2011b; Takacs et al, 2013; Pallagi et al, 2014; Maleth et al, 2015). Much less is known about the water transport processes, despite the fact that movement of electrolytes is osmotically coupled to water flow

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