Abnormal Distribution of Aquaporin-5 Water Channel Protein in Salivary Glands from Sjögren's Syndrome Patients

Steinfeld, Serge; Cogan, Elie; King, Landon S.; Agre, Peter; Kiss, Róbert; Delporte, Christine

doi:10.1038/labinvest.3780221

Cited by 256 publications

(231 citation statements)

References 36 publications

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“…18). AQP5 down-regulation in patients with Sjögren's syndrome has been observed by microarray analysis of MSGs from patients with pSS, and altered distribution of the channel has been described by histological studies in patients and mice overexpressing BMP6 (10,19). In addition, the increased expression of AQP5 has been described in patients with pSS successfully treated with rituximab, suggesting a central role for this protein in gland recovery (20).…”

Section: Resultsmentioning

confidence: 90%

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Lai

Yin

Cabrera-Pérez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjögren’s syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjögren’s syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjögren’s syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjögren’s syndrome.

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Section: Resultsmentioning

confidence: 90%

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Lai

Yin

Cabrera-Pérez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Consequently, the increased UWS flow seen following IFN alfa treatment may be due to an upregulation of AQP5, with highly selective water channel proteins reported to be abnormally distributed in lacrimal and salivary glands of Sjö gren's syndrome patients (35,36).…”

Section: Cummins Et Almentioning

confidence: 99%

Treatment of primary sjögren's syndrome with low‐dose human interferon alfa administered by the oromucosal route: Combined phase III results

Cummins

Papas

Kammer

et al. 2003

Arthritis & Rheumatism

123

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Objective. This study tested the safety and efficacy of human interferon (IFN) alfa for treatment of salivary hypofunction and dry mouth symptoms in primary Sjö gren's syndrome patients. Methods. Combined results are reported from 2 phase III clinical trials in which a total of 497 subjects with primary Sjö gren's syndrome received 150 international units of human IFN alfa or matching placebo 3 times per day for 24 weeks by the oromucosal route. Results. Subjects given IFN alfa had a significantly (P ‫؍‬ 0.01) greater mean increase in unstimulated whole saliva (UWS) flow, compared with subjects given placebo. In IFN alfa patients, increases in UWS correlated positively and significantly with improvements noted in 7 of 8 symptoms associated with oral and ocular dryness. The coprimary endpoints of stimulated whole saliva flow and oral dryness were not significantly improved in the IFN alfa group relative to placebo. No significant differences were found between the groups with respect to overall adverse event incidence or severity. Conclusion. IFN alfa given at low dosage by the oromucosal route can significantly increase UWS flow in patients with primary Sjö gren's syndrome, without causing significant adverse events.

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“…The observation of gender-specific differences in paracellular permeability and TJC composition in mice is of particular interest in the context of the human salivary disorder xerostomia (drymouth), because AQP5 has been implicated as a component of this syndrome (41)(42)(43). Drymouth, a component of Sjögren's syndrome, affects women at a significantly higher frequency and with greater severity than it affects men (44,45).…”

Section: Gender-specific Differences In the Properties Of Paracellulamentioning

confidence: 99%

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

Kawedia

Nieman²,

Boivin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

121

100

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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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Abnormal Distribution of Aquaporin-5 Water Channel Protein in Salivary Glands from Sjögren's Syndrome Patients

Cited by 256 publications

References 36 publications

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Treatment of primary sjögren's syndrome with low‐dose human interferon alfa administered by the oromucosal route: Combined phase III results

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

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