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      Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma

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          Abstract

          Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H 2O 2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3 −/−) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3 −/− mice compared with wild-type mice after OVA challenge, consistently with fewer CD4 + T cells from AQP3 −/− mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H 2O 2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target.

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          Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling.

          Hydrogen peroxide (H(2)O(2)) produced by cell-surface NADPH Oxidase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H(2)O(2) to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H(2)O(2) into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl-Ester (PY1-ME), a new chemoselective fluorescent indicator for H(2)O(2), directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H(2)O(2) specifically through membranes in mammalian cells. Moreover, we show that intracellular H(2)O(2) accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Nox-derived H(2)O(2) signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H(2)O(2) can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions.
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            A current view of the mammalian aquaglyceroporins.

            The discovery of aquaporin water channels by Agre and coworkers answered a long-standing biophysical question of how the majority of water crosses biological membranes. The identification and study of aquaporins have provided insight, at the molecular level, into the fundamental physiology of water balance regulation and the pathophysiology of water balance disorders. In addition to the originally identified classical aquaporins, a second class of aquaporins has been identified. Aquaporins in this latter class, the so-called aquaglyceroporins, transport small uncharged molecules such as glycerol and urea as well as water. Aquaglyceroporins have a wide tissue distribution, and emerging data suggest that several of them may play previously unappreciated physiological or pathophysiological roles. Analyses of transgenic mice have revealed potential roles of aquaglyceroporins in skin elasticity, gastrointestinal function and metabolism, and metabolic diseases such as diabetes mellitus. This review comprehensively discusses the recent discoveries in the field of aquaglyceroporins, alongside a brief overview of the so-called unorthodox aquaporins.
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              Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice.

              Mice deficient in the epidermal water/glycerol transporter aquaporin-3 (AQP3) have reduced stratum corneum (SC) hydration and skin elasticity, and impaired barrier recovery after SC removal. SC glycerol content is reduced 3-fold in AQP3 null mice, whereas SC structure, protein/lipid composition, and ion/osmolyte content are not changed. We show here that glycerol replacement corrects each of the defects in AQP3 null mice. SC water content, measured by skin conductance and 3H2O accumulation, was 3-fold lower in AQP3 null vs. wild-type mice, but became similar after topical or systemic administration of glycerol in quantities that normalized SC glycerol content. SC water content was not corrected by glycerol-like osmolytes such as xylitol, erythritol, and propanediol. Orally administered glycerol fully corrected the reduced skin elasticity in AQP3 null mice as measured by the kinetics of skin displacement after suction, and the delayed barrier recovery as measured by transepidermal water loss after tape-stripping. Analysis of [14C]glycerol kinetics indicated reduced blood-to-SC transport of glycerol in AQP3 null mice, resulting in slowed lipid biosynthesis. These data provide functional evidence for a physiological role of glycerol transport by an aquaglyceroporin, and indicate that glycerol is a major determinant of SC water retention, and mechanical and biosynthetic functions. Our findings establish a scientific basis for the >200-yr-old empirical practice of including glycerol in cosmetic and medicinal skin formulations.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                11 May 2016
                2016
                : 6
                : 25781
                Affiliations
                [1 ]Department of Respiratory Medicine, Kyoto University Graduate School of Medicine , Sakyo-ku, Kyoto 606-8507, Japan
                [2 ]Department of Respiratory Care and Sleep Control Medicine, Kyoto University Graduate School of Medicine , Sakyo-ku, Kyoto 606-8507, Japan
                [3 ]Department of Dermatology, Kyoto University Graduate School of Medicine , Sakyo-ku, Kyoto 606-8507, Japan
                [4 ]Center for Innovation in Immunoregulative Technology and Therapeutics (AK project), Kyoto University Graduate School of Medicine , Sakyo-ku, Kyoto 606-8501, Japan
                [5 ]Core Research for Evolutional Science and Technology (CREST) Laboratory, Medical Innovation Center, Kyoto University Graduate School of Medicine , Sakyo-ku, Kyoto 606-8501, Japan
                [6 ]Center for anatomical, forensic and pathology research, Kyoto University Hospital , Sakyo-ku, Kyoto 606-8501, Japan
                [7 ]Louis Pasteur Center for Medical Research , Sakyo-ku, Kyoto 606-8225, Japan
                [8 ]Bioresearch Center, CMIC Pharma Science Co., Ltd. , Hokuto-shi, Yamanashi 408-0044, Japan
                [9 ]Department of Respiratory Medicine, Tenri Hospital , Tenri-shi, Nara 632-8552, Japan
                [10 ]Departments of Medicine and Physiology, University of California , San Francisco, CA 94143, USA
                Author notes
                Article
                srep25781
                10.1038/srep25781
                4863152
                27165276
                4b667466-2bb7-416d-b87e-3fcf3922247e
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 17 November 2015
                : 22 April 2016
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