NDT Advance Access originally published online on April 20, 2006
Nephrology Dialysis Transplantation 2006 21(8):2069-2071; doi:10.1093/ndt/gfl162
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Translational Nephrology
Aquaporin-1—a water channel on the move*
Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels, Belgium
Correspondence and offprint requests to: Olivier Devuyst, MD, PhD, Service de Néphrologie, Université catholique de Louvain, Avenue Hippocrate 10, B-1200 Bruxelles, Belgique. Email: devuyst{at}nefr.ucl.ac.be
Keywords: cell migration; endothelium; proximal tubule; angiogenesis; wound healing; water transport
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Aquaporin-1, a water channel involved in urinary concentrating ability |
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 Top Aquaporin-1, a water channel... From water handling to...How aquaporins could participate...ConclusionsReferences |
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The aquaporins (AQPs) constitute a family of transmembrane, channel-forming glycoproteins, which provide a molecular pathway for the rapid transport of water across biological membranes. These proteins are conserved in bacteria, plants and mammals [1]. The first AQP was identified in 1988 by Peter Agre and his colleagues [2], who were at the time investigating the Rhesus blood group antigens. Using antibodies raised against proteins from the membranes of red blood cells, they purified a peculiar protein that was located in the proximal tubules and descending thin limbs of Henle's loop, i.e. in the exact nephron segments harbouring a constitutive water permeability [2]. After cloning the cDNA and analysing the predicted 269 amino acid polypeptide, they called the newly identified protein ‘CHIP28’ for CHannel-like Integral membrane Protein of 28 kDa. CHIP28 was then expressed into oocytes from Xenopus laevis—the rapid swelling and explosion of the CHIP28 oocytes when transferred to a hypotonic buffer demonstrated that the protein was indeed the first identified water channel [3]. CHIP28 was soon renamed ‘aquaporin-1’ (AQP1) and, in 2003, Peter Agre shared the Nobel Prize in Chemistry for this seminal discovery.
To date, 13 members of the AQP family have been identified in mammals. Most AQPs are exclusively permeable to water, whereas some isoforms (AQP3, AQP5, AQP9 and AQP10, called ‘aquaglyceroporins’) transport water, glycerol, urea and possibly other small solutes [4]. The mechanism of selective permeability of these channels for water and/or glycerol has been documented by high-resolution crystallography [5]. With the exception of AQP2, whose membrane expression is regulated by the antidiuretic hormone arginine vasopressin (AVP), most AQPs are constitutively expressed in the plasma membrane [1,4]. In the kidney, AQP1 mediates osmotically driven water transport across the epithelial cells lining the proximal tubules and descending thin limbs of Henle's loop, and the endothelial cells lining the descending vasa recta [6,7]. The physiological importance of AQP1 in the kidney is demonstrated by the nephrogenic diabetes insipidus observed in mice knockout (KO) for Aqp1 [8] and in Colton-null patients who lack functional AQP1 due to homozygous nonsense mutations in the AQP1 gene [9].
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From water handling to angiogenesis and cell migration |
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TopAquaporin-1, a water channel...From water handling to...How aquaporins could participate...ConclusionsReferences |
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Outside the kidney, AQP1 is abundantly expressed in the endothelial cells lining non-fenestrated capillaries in several organs outside the central nervous system [10]. Studies in Aqp1 KO mice demonstrated that, in given experimental conditions, AQP1 mediates osmotically induced water transport across the endothelial barrier in serosal membranes such as the pleura and the peritoneum, in lung microvessels and in the cornea [11]. The relevance of these findings to physiological processes is probably limited or depends on peculiar clinical settings [1,11]. However, AQP1 is potentially important for patients in end-stage renal disease—the ultrasmall pore constituted by AQP1 indeed plays an essential role in water permeability and ultrafiltration during peritoneal dialysis [12].
A set of recent studies has revealed an unexpected role of AQP1 in cell migration. AQP1 was known to be highly expressed in proliferating tumour microvessels, suggesting that it may play a role in tumour angiogenesis [13]. To test that hypothesis, Saadoun et al. [14] implanted melanoma cells in Aqp1 mice. They observed reduced tumour growth, due to reduced microvessel proliferation causing extensive tumour necrosis, and improved survival in Aqp1 KO mice [14]. The altered angiogenesis was confirmed when the Aqp1 KO mice were implanted with Matrigel® pellets containing angiogenic factors, i.e. in a non-tumoural model. In a reverse experiment, stable transfection of non-endothelial cells with AQP1 or with another water channel (AQP4) accelerated cell migration and wound healing in vitro, indicating that the effect is not AQP or cell-type specific [14]. Further evidence that AQP-dependent cell migration might be a more general phenomenon was suggested by the demonstration of the role of AQP4 in astroglial cell migration, which occurs during glial scar formation in brain injury [15]. The AQP1-facilitated cell migration may also be important in the kidney, since the migration of proximal tubule (PT) cell cultured from Aqp1 KO mice was reduced compared with wild-type cells, without changes in proliferation and adhesiveness [16]. These findings had an in vivo counterpart, since unilateral ischaemia–reperfusion induced a more severe PT damage and delayed restitution of PT structure in the Aqp1 KO mice [16].
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How aquaporins could participate in cell migration |
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Many cell types are able to generate transient membrane protrusions (lamellipodia and membrane ruffles) at their front end, coupled to transient retractions at the rear end, resulting in directional displacement (Figure 1). In parallel with these cytoskeletal mechanisms, cell migration also involves the activity of ion channels and transporters, which participate in cell volume regulation while being themselves regulated by actin filaments [17]. Studies of neutrophil leucocyte motility supported a pivotal role of AQP-mediated water fluxes in the formation of membrane protrusions [18]. Furthermore, the polarized expression of AQP1 may accelerate the turnover of cell membrane protrusions at the leading edge of non-endothelial cells stably transfected with AQP1 [14]. Conversely, a reduced appearance of membrane protrusions was observed in AQP1-deficient PT cell cultures [16]. Based on these data, one can suggest that actin cleavage and ion uptake at the tip of a lamellipodium may create local osmotic gradients driving AQP-mediated water influx which, in turn, would increase the local hydrostatic pressure, causing cell membrane protrusions, creating space for actin polymerization and promoting cell migration (Figure 1) [14,17].
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(AE1) exchangers and the electrogenic Na+-
cotransporter (NBC1, with a 1:3 stoechiometry) at the front of migrating cells mediates water intake via the water channel AQP1, and an osmotic swelling. This chain of event stretches the plasma membrane and increases intracellular Ca2+ concentration, triggering cystoskeletal mechanisms leading to the shrinkage of the rear pole of the cell and migration along a given axis. ECM, extracellular matrix (Modified from [ |
Conclusions |
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Thus far, AQP1 was essentially considered as a water channel involved in the urinary concentrating mechanism. However, recent studies have demonstrated that AQP1 also plays unexpected roles in endothelial and non-endothelial cell types, with a potential relevance in physiology and pathophysiology. AQP1 may play a role in cell migration and wound healing [14], including the response of renal PT cells to injury [16]. Because the structure of AQP1 has been exquisitely detailed [1,5], there are real perspectives for pharmacological targeting. As suggested by Saadoun et al. [14], targeting AQP1 could limit tumour growth and dissemination. Alternatively, in non-tumoural tissues, it may be interesting to up-regulate the expression of AQP1. For instance, the induction of AQP1 by corticosteroids may play a role in the neonatal maturation of the lung [19] and improve water transport in uraemic patients treated by peritoneal dialysis [20]. Likewise, the induction of AQP1 expression in non-tumoural cells may accelerate wound healing and facilitate organ regeneration, for example, after acute renal injury [14,16].
Conflict of interest statement. None declared.
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Notes |
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*Comment on Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 2005; 434: 786–792
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[Abstract/Free Full Text]
Accepted in revised form: 13. 3.06
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