Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex

Abstract

To investigate potential physiological interactions between the transcellular and paracellular pathways of water transport, we asked whether targeted deletion of Aquaporin 5 (AQP5), the major transcellular water transporter in salivary acinar cells, affected paracellular transport of 4-kDa FITC-labeled dextran (FITC-D), which is transported through the paracellular but not the transcellular route. After i.v. injection of FITC-D into either AQP5 wild-type or AQP5؊/؊ mice and saliva collection for fixed time intervals, we show that the relative amount of FITC-D transported in the saliva of AQP5؊/؊ mice is half that in matched AQP5؉/؉ mice, indicating a 2-fold decrease in permeability of the paracellular barrier in mice lacking AQP5. We also found a significant difference in the proportion of transcellular vs. paracellular transport between male and female mice. Freeze-fracture electron microscopy revealed an increase in the number of tight junction strands of both AQP5؉/؉ and AQP5؊/؊ male mice after pilocarpine stimulation but no change in strand number in female mice. Average acinar cell volume was increased by Ϸ1.4-fold in glands from AQP5؊/؊ mice, suggesting an alteration in the volumesensing machinery of the cell. Western blots revealed that expression of Claudin-7, Claudin-3, and Occludin, critical proteins that regulate the permeability of the tight junction barrier, were significantly decreased in AQP5؊/؊ compared with AQP5؉/؉ salivary glands. These findings reveal the existence of a genderinfluenced molecular mechanism involving AQP5 that allows transcellular and paracellular routes of water transport to act in conjunction.epithelium ͉ fluid absorption and secretion T he proper transport of electrolytes and water across epithelial barriers is of vital importance to the maintenance of normal physiological homeostasis in all animals (1, 2). Fluid is moved either across the plasma membranes of the cells that comprise the epithelial layer (transcellular transport) or between these cells, through the tight junction complex (TJC) that forms a barrier (paracellular transport). Together, the transcellular and paracellular pathways are capable of transporting large volumes of fluid, estimated at 200 liters per day in a 70-kg human (1).There is considerable complexity in the mechanisms that determine the usage of paracellular vs. transcellular routes of water transport. For example, in the kidney, transport of water is accomplished mainly through paracellular transport in the proximal nephron (3), whereas highly regulated transcellular transport is carried out in the distal nephron and collecting duct (4). Similar complexities are likely to exist in the secretion and absorption of water in the gut and the secretion of fluids by exocrine glands such as the salivary gland and pancreas.In an attempt to determine the ratio of paracellular to transcellular transport, Murakami et al. (5,6) used ex vivo perfused rat submandibular salivary glands and showed that the majority of water is transported through the paracellular ...

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