Aquaporin 11, a regulator of water efflux at retinal Müller glial cell surface decreases concomitant with immune-mediated gliosis

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Abstract

Background

Müller glial cells are important regulators of physiological function of retina. In a model disease of retinal inflammation and spontaneous recurrent uveitis in horses (ERU), we could show that retinal Müller glial cells significantly change potassium and water channel protein expression during autoimmune pathogenesis. The most significantly changed channel protein in neuroinflammatory ERU was aquaporin 11 (AQP11). Aquaporins (AQP, 13 members) are important regulators of water and small solute transport through membranes. AQP11 is an unorthodox member of this family and was assigned to a third group of AQPs because of its difference in amino acid sequence (conserved sequence is only 11 %) and especially its largely unknown function.

Methods

In order to gain insight into the distribution, localization, and function of AQP11 in the retina, we first developed a novel monoclonal antibody for AQP11 enabling quantification, localization, and functional studies.

Results

In the horse retina, AQP11 was exclusively expressed at Müller glial cell membranes. In uveitic condition, AQP11 disappeared from gliotic Müller cells concomitant with glutamine synthase. Since function of AQP11 is still under debate, we assessed the impact of AQP11 channel on cell volume regulation of primary Müller glial cells under different osmotic conditions. We conclude a concomitant role for AQP11 with AQP4 in water efflux from these glial cells, which is disturbed in ERU. This could probably contribute to swelling and subsequent severe complication of retinal edema through impaired intracellular fluid regulation.

Conclusions

Therefore, AQP11 is important for physiological Müller glia function and the expression pattern and function of this water channel seems to have distinct functions in central nervous system. The significant reduction in neuroinflammation points to a crucial role in pathogenesis of autoimmune uveitis.

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Most cited references 33

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Aquaporin water channels in mammals.

S Kondo, Kenichi Ishibashi, S Hara (2009)

Water channels, aquaporins (AQPs), are a family of small integral plasma membrane proteins that primarily transport water across the plasma membrane. There are 13 members (AQP0-12) in humans. This number is final as the human genome project has been completed. They are divided into three subgroups based on the primary sequences: water selective AQPs (AQP0, 1, 2, 4, 5, 6, 8), aquaglyceroporins (AQP3, 7, 9, 10), and superaquaporins (AQP11, 12). Since no specific inhibitors are yet available, functional roles of AQPs are suggested by AQP null mice and humans. Abnormal water metabolism was shown with AQP1, 2, 3, 4, 5 null mice, especially with AQP2 null mice: fatal at neonate due to diabetes insipidus. Abnormal glycerol transport was shown with AQP3, 7, 9 null mice, although they appeared normal. AQP0 null mice suffer from cataracts, although the pathogenesis is not clear. Unexpectedly, AQP11 null mice die from uremia as a result of polycystic kidneys. Interestingly, AQP6, 8, 10, 12 null mice are almost normal. AQP null humans have been reported with AQP0, 1, 2, 3, 7: only AQP2 null humans show an outstanding phenotype, diabetes insipidus. This review summarizes the current knowledge on all mammalian AQPs and hopefully will stimulate future research in both clinical and basic fields.

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Human aquaporins: regulators of transcellular water flow.

Brandon Marshall, Alex C. Conner, Philip Kitchen … (2014)

Emerging evidence supports the view that (AQP) aquaporin water channels are regulators of transcellular water flow. Consistent with their expression in most tissues, AQPs are associated with diverse physiological and pathophysiological processes. AQP knockout studies suggest that the regulatory role of AQPs, rather than their action as passive channels, is their critical function. Transport through all AQPs occurs by a common passive mechanism, but their regulation and cellular distribution varies significantly depending on cell and tissue type; the role of AQPs in cell volume regulation (CVR) is particularly notable. This review examines the regulatory role of AQPs in transcellular water flow, especially in CVR. We focus on key systems of the human body, encompassing processes as diverse as urine concentration in the kidney to clearance of brain oedema. AQPs are crucial for the regulation of water homeostasis, providing selective pores for the rapid movement of water across diverse cell membranes and playing regulatory roles in CVR. Gating mechanisms have been proposed for human AQPs, but have only been reported for plant and microbial AQPs. Consequently, it is likely that the distribution and abundance of AQPs in a particular membrane is the determinant of membrane water permeability and a regulator of transcellular water flow. Elucidating the mechanisms that regulate transcellular water flow will improve our understanding of the human body in health and disease. The central role of specific AQPs in regulating water homeostasis will provide routes to a range of novel therapies. This article is part of a Special Issue entitled Aquaporins. © 2013. Published by Elsevier B.V. All rights reserved.

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Müller cell changes in human diabetic retinopathy.

M Mizutani, C Gerhardinger, M. Lorenzi (1998)

Vascular cells may not be the only cells affected by diabetes in the retina. In particular, abnormalities of the b-wave of the electroretinogram in diabetic patients with absent or minimal microangiopathy have pointed to possible dysfunction of Müller cells, the principal glia of the retina. In this study, we sought evidence for diabetes-induced Müller cell abnormalities by testing the expression of three proteins (Bcl-2, glutamine synthetase [GS], and glial fibrillar acidic protein [GFAP]) that are solely or predominantly expressed in Müller cells and show a reproducible pattern of changes in the context of retinal injuries or degenerations. Retinas obtained postmortem from a total of 14 donors aged 65 +/- 6 years with 10 +/- 4 years of diabetes and histological evidence of microangiopathy and 18 age-matched nondiabetic donors were examined by immunohistochemistry and immunoblotting. The typical Müller cell pattern of Bcl-2 and GS immunostaining was similar for both intensity and distribution in the nondiabetic and diabetic retinas, as were the levels of the two proteins. In contrast, GFAP staining, largely confined to the most proximal retina in the nondiabetic donors, was in most diabetic retinas present along the entire length of the Müller cell processes, throughout the outer retina. Accordingly, the level of GFAP was increased in the diabetic retinas (161 +/- 106 densitometric units/microg protein vs. 55 +/- 45 in the nondiabetic retinas, P = 0.03). These data provide evidence for selective biosynthetic changes of Müller glial cells in diabetes. Because Müller cells produce factors capable of modulating blood flow, vascular permeability, and cell survival, and their processes surround all blood vessels in the retina, a possible role of these cells in the pathogenesis of retinal microangiopathy deserves to be investigated.

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Author and article information

Contributors

Cornelia A. Deeg: + 49 (0)6421-5863944 , + 49 (0)6421-5865678 , Cornelia.Deeg@uni-marburg.de

Barbara Amann: baerbl.amann@tiph.vetmed.uni-muenchen.de

Konstantin Lutz: Lutz@tiph.vetmed.uni-muenchen.de

Sieglinde Hirmer: Sieglinde.Hirmer@lrz-muenchen.de

Karina Lutterberg: k.lutterberg@tiph.vetmed.uni-muenchen.de

Elisabeth Kremmer: krexit-hmgu@outlook.de

Stefanie M. Hauck: hauck@helmholtz-muenchen.de

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 23 April 2016

Publication date PMC-release: 23 April 2016

Publication date Collection: 2016

Volume: 13

Electronic Location Identifier: 89

Affiliations

[ ]Experimental Ophthalmology, Philipps University of Marburg, Baldingerstrasse, 35033 Marburg, Germany

[ ]Department of Veterinary Sciences, Institute of Animal Physiology, Ludwig-Maximilians University, Veterinärstr. 13, 80539 München, Germany

[ ]Helmholtz Zentrum München—German Research Center for Environmental Health (GmbH), Institute for Molecular Immunology, Marchioninistraße 25, 81377 München, Germany

[ ]Department of Protein Science, Helmholtz Zentrum München—German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany

Article

Publisher ID: 554

DOI: 10.1186/s12974-016-0554-2

PMC ID: 4842293

PubMed ID: 27107718

SO-VID: f2676870-ec4a-460e-9f89-5e2c486f84d3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 January 2016

Date accepted : 18 April 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: DE 719/2-1, SFB 571 A5

Award Recipient : Cornelia A. Deeg

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: aqp11,aqp4,aqp5,water efflux,cell volume regulation,water channel,superaquaporin,autoimmune uveitis,retinal inflammation

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: aqp11, aqp4, aqp5, water efflux, cell volume regulation, water channel, superaquaporin, autoimmune uveitis, retinal inflammation

Aquaporin 11, a regulator of water efflux at retinal Müller glial cell surface decreases concomitant with immune-mediated gliosis

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Most cited references 33

Aquaporin water channels in mammals.

Human aquaporins: regulators of transcellular water flow.

Müller cell changes in human diabetic retinopathy.

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