Issue 2, pages 112–133, February 2009 2009, 61(2): 112–133, 2009 2B5f water

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AQP6 was found180 in the intracellular vesicles of acid-secreting intercalated cells of the RCD colocalized with the H+-ATPase, a protein that participates in the secretion of acid in the urine. AQP6 seemed to be a Hg2+-inhibitable Water channel [Ma et al.,1993, cited in51]. Later, it was found that AQP6 is also permeated by anions and channel function is activated by Hg2+ and low pH [Yasui et al., 1999, cited in171]. Lui et al., 2005 [cited in51] found that, in contrast to previous studies, AQP6 does not allow Water to permeate, but that a mutation of a single residue (a change of Asn-60 to Gly converts AQP6 from an anion channel to a Water channel. The majority of studies would characterize AQP6 as a unique, Hg2+-and low pH-activated, multipermeable channel. AQP6 was recently included among the “unorthodox” AQPs51. It was speculated that AQP6 may play a role in the body acid–base homeostasis171.

AQP7 [that was originally discovered in seminiferous tubules by Ishibashi et al.181] was found in the kidney colocalized with AQP1 in the brush border of the proximal tubule [Nejsum et al., 2000; Ishibashi et al., 2000, cited in51]. The main physiological role of AQP7 in the kidney is related to glycerol reabsorption51. AQP7-KO mice show greatly increased glycerol excretion182.

AQP8 is localized intracellularly in proximal tubules and RCD, however its cellular localization (in mitochondria) and regulation of targeting are topics of dispute [see discussions in51]. AQP8 can be permeated by NH3; however this may not be physiologically relevant because the AQP8 disruption did not lead to changes in NH3 metabolism [Yang et al., 2006, cited in51]. AQP8 was recently included among the “unorthodox” AQPs51.

AQP11 was found in the cytoplasm of the proximal tubule cells and, although its exact function is not known, the deletion of AQP11 gene produces a severe phenotype: AQP11-KO mice dye with polycystic kidneys following vacuolization of the proximal tubule183.

The gastrointestinal system accomplishes (next to kidney) the second largest amount of total fluid absorption and secretion. Substantial quantities of fluid are secreted into the gastrointestinal tract by salivary gland, stomach, pancreas and the hepatobiliary tree and the majority of secreted fluid is absorbed by the small intestine and colon to produce a dehydrated feces173.

The salivary gland expresses several aquaporins including AQP1 in microvascular endothelia, AQP4 in ductal epithelia, and AQP5 at the apical membrane of serous acinar cells. It seems that only AQP5 has a role in saliva secretion, since in the AQP5-null mice saliva secretion was remarkably reduced, but unimpaired in AQP1 or AQP4-null mice173. AQP5 is also expressed in the apical membrane of tear-secreting cells of the lacrimal gland and was implicated in the pathophysiology of Sjögren's syndrome (an autoimmune disease characterized by dry eyes and a dry mouth). two groups of investigators reported a decrease in AQP5 levels in the salivary gland [Steinfeld et al., 2001, cited in171] and lacrimal gland secretory cells [Tsubota et al., 2001, cited in171]. However, a third group found no difference in the AQP5 distribution in salivary gland of a larger cohort of patients with Sjögren's syndrome compared with control subjects [Beroukas et al., 2001, cited in171].

AQP4 is expressed in the stomach parietal cells, where stomach acid is produced; however AQP4 does not appear to facilitate gastric acid production. AQP4 is also expressed in the colon, probably playing a minor role in the dehydration of feces173.

AQP3, AQP5, AQP8, AQP9, and AQP10 have also been found in the epithelium along the GI tract; out of these, AQP10 is expressed exclusively in the small intestine, in the absorptive epithelial cells171.

AQP1 was reported to be expressed at several sites in the proximal GI tract, possibly playing a role in dietary fat processing, including cholangiocytes in the liver (bile production), pancreatic microvascular endothelium (pancreatic fluid production), intestinal lacteals (chylomicron absorption) and gallbladder (bile storage)173. Recently, Jin et al.184 described a broad distribution of AQP1 in epithelium and endothelium of porcine digestive organs, and suggested an important role in fluid secretion/absorbtion, as well as in digestive function and pathophysiology of the GI system. However, this work was critically evaluated by Mobasheri185.

Other aspects regarding WCPSs in the GI tract and organs are discussed by Koyama et al., 1999; Ma and Verkman, 1999; Matsuzaki et al., 2004, [cited in171]; see also ref.186, for a review on WCPSs in the exocrine pancreas and refs.187, 188 for reviews on WCPSs in control of volume in secretory vesicles.

The respiratory apparatus (airways, lung, pleura) has potentially important sites of fluid movement in airway hydration, reabsorption of alveolar fluid in the neonatal period, formation/resolution of pulmonary edema, resulting from heart failure or lung injury, pleural fluid secretion/reabsorbtion and accumulation in pathological conditions189. In the upper respiratory tract, the epithelium of the nasopharynx and trachea has AQP3 in basal cells, AQP4 in the basolateral membrane of ciliated columnar cells, and secretory cells in the submucosal glands, and AQP5 in the apical membrane of these secretory cells. In the epithelium of distal airways there is only AQP4, whereas in the alveolar epithelium AQP5 is present in the apical membrane of type-I pneumocytes. AQP1 is present in pleura and microvessels (capillaries and venules) throughout all components of the respiratory apparatus [reviewed in171, 188]. This expression pattern of WCPSs provides indirect evidence for their involvement in fluid handling by lung and airways. Several other lines of evidence appear to support physiological roles of AQPs in lung and airways. The expression of lung AQPs is developmentally regulated with distinct patterns for each AQP. AQP1 is detectable just before birth in rodents, increasing several-fold perinatally and into adulthood, while rabbit lung Water permeability in the perinatal period parallelled increasing AQP1 expression. AQP4 strongly increases just after birth and is upregulated by β-agonists and glucocorticoids; in contrast, little AQP5 is expressed at birth and gradually increases until adulthood [see citations in189]. Many other observations of increased or decreased expression of lung AQPs induced by growth factors, inflammatory mediators, viral infection, osmotic stress, lipopolysaccaride or nickel-induced lung injury, cAMP, tumor necrosis factor-α have been published [reviewed in171, 189]. However, studies on aquaporin null-mice suggested that although AQPs provide a major route for osmotically-driven Water transport among the airspace, interstitial and capillary compartments, AQP1, AQP3, and AQP4 are not required for physiologically important lung functions189. A notable exception is AQP5, wich appeared to be important in fluid secretion by submucosal glands in the upper airways. Consequently, modulation of AQP5 expression or function could provide a novel therapy to change the volume and viscosity of fluid secretions in cystic fibrosis and infections of allergic rhinitis189.

WCPSs in the central nervous system (CNS) appear to be of great physiological and pathological importance, considering the rigid physical constraint that is imposed to the brain by the bony cranium and that ∼80% of the brain is Water190.

In rodent brain cells seven WCPSs have been described: AQP1, AQP3, AQP4, AQP5, AQP8, AQP9, and AQP11, however only three have been clearly identified in the apical (but not the basolateral) membrane of brain cells in vivo: AQP1, AQP4, and AQP9191.

AQP1 is expressed in epithelial cells of the choroid plexus (CP)192 and is probably involved in the cerebrospinal fluid (CSF) formation193. This idea is supported by the increased CSF production in CP tumours in parallel with increased expression of AQP1. As hydrocephalus is associated with CSF flow abnomalities, inhibitors of AQP1 might be useful in treating this disease190. Interestingly, AQP1 is not found in the normal brain capillary endothelium, although is highly expressed in peripheral endothelial cells. AQP1 is present in capillaries and astrocytes of astrocytomas and metastatic carcinomas194. AQP1 was also found in small-diameter sensory neurons in dorsal root, trigeminal and nodose ganglia and colocalized with markers of nociceptors, notably substance P. Impaired pain sensation in AQP1-null mice has been reported by Oshio et al. 2006, [cited in195]. It was therefore suggested that AQP1 may be involved in the pathophysiology of migraine195.

AQP4 is expressed strongly throughout the brain and spinal cord, especially in astroglial cells lining ependyma and pial surfaces in contact with the CSF and the blood-brain barrier, in glial cells forming the edge of the cerebral cortex and brainstem, vasopressin-secretory neurons in supraoptic and paraventricular nuclei of the hypothalamus, and Purkinje cells of cerebellum190. This pattern of distribution is in agrement with the major role of AQP4 to control Water movements into and out of the brain.

A role of AQP4 in the generation of brain edema in response to two established neurological insults (acute Water intoxication and ischemic stroke) has been proposed196. AQP4-null mice appeared to be protected from brain edema in both models, with improved clinical outcome and reduced brain swelling [reviewed in173]. On the other hand, several studies have shown that the expression of AQP4 is reduced or increased after ischemia-induced brain edema depending on the brain region and the time after the onset of the ischemic insult [Frydenlund et al., 2006; Ribeiro et al., 2006, cited in197]. Reduced brain swelling after cerebral ischemia and Water intoxication has also been reported in α-syntrophin-null mice, which have reduced AQP4 expression in astrocyte foot processes [Amiry-Moghaddam et al, 2003; 2004, cited in190]. In contrast to its beneficial role in cytotoxic edema, AQP4 deficiency produces more brain swelling in mouse models of vasogenic edema, including brain tumor, infusion of normal saline into brain extracellular space and focal cortical freze injury [Papadopoulous et al., 2004, cited in190]. Based on the earlier discussion it was suggested that AQP4 inhibitors may reduce cytotoxic brain swelling in humans, whereas AQP4 activators or upregulators may reduce vasogenic edema and hydrocephalus190.

A second role of AQP4, in astrocyte migration, has been suggested based on impaired migration of cultured AQP4-null astrocytes compared to wild-type astrocytes. On the other hand AQP4 overexpression is a feature of astrocytomas, facilitates cancer spread and AQP inhibitors may slow tumor growth190.

A third role of AQP4 in brain was suggested to be the control of neuronal activity. It has been proposed that altered K+ kinetics in brain ECS account for the altered neuronal activity in AQP4 deficiency [reviewed in190, 191]. In vivo, AQP4-null mice have delayed K+ clearance from brain ECS after local electrical stimulation [Binder et al., 2006, cited in190] and during cortical excitation by spreading depression [Padmawar et al., 2005, cited in190]. Hippocampal slices from α-syntrophin-null mice also have slowed K+ kinetics after evoked neuronal activity, and the altered K+ kinetics in AQP4 deficiency has been explained by a functional association between AQP4-facilitated Water movement and K+ movement through the Kir4.1 [Amiry-Moghaddam et al., 2003, cited in190]. However, no functionally significant interactions between AQP4 and Kir4.1 were found [reviewed in190].

ECS expansion has recently been proposed as an alternative mechanism to account for higher seizure threshold and prolonged seizure duration in AQP4 deficiency198. An increased ECS volume increases the buffering capacity for K+ released into the ECS during neuronal excitation, preventing large changes in ECS [K+]. It is unclear, however, why the ECS volume is increased in AQP4-null mice190. All these findings confirm our earlier conclusion of a membrane defect affecting Water permeability in epilepsy [reviewed in199]. The seizure phenotype data in AQP4-deficient mice raise the possibility that AQP4 modulation may also be effective in epilepsy therapy197.

Another physiological role has been suggested for AQP4 in cell ADHesion between astrocytes and endothelial cells or muscle cells in the perivascular compartment. The presence of AQP4 of the endfoot membrane is dependent upon the presence of proteins in the basal lamina such as agrin, α-dystroglycan and laminin [Guadagno and Moukhes, 2004, cited in191], suggesting an involvement of AQP4 in the ability of astrocytes to maintain the integrity of blood-brain barrier.

Recently, it has been found that autoimmune reactions with autoantibodies against AQP4 appear to produce neuromyelitis optica (Devic's disease) and the presence of these autoantibodies is a criterion for differential diagnosis with multiple sclerosis200.

AQP9 has been observed in three cell types: endothelial cells of sub-pial vessels, glial cells (in particular tanycytes and astrocytes), and neurons [reviewed in191]. AQP9 expression was found predominantly in one subtype of neurons, the catecholaminergic neurons [Badaut et al., 2004, cited in191]. These neurons are involved in energy balance [Grill and Kaplan, 2002, cited in191]. Consequently, a role for AQP9 in brain energy metabolism have recently been proposed. AQP9 facilitate the transport of lactate across the astrocyte membrane and lactate diffuses to neurons for energy consumption [Pellerin et al., 2007, cited in190]. AQP9 permeability to Water, glycerol and lactate may be important in brain ischemia. Lactic acidosis during ischemia may increase the permeability of AQP9 and enable uptake of excess lactate by astrocytes.

Water homeostasis in the eye, involving protection of the epithelium, regulation of intraocular fluid levels and pressure, maintaining the transparency of the pathway for light (cornea and lens), retinal signal transduction, are crucial processes for the normal functioning of the eye201.

The cornea consists of a stromal layer, covered at its external surface by an epithelium, in contact with tear fluid, and at its inner surface by an endothelium, in contact with aqueous humor (AH) (the fluid in anterior eye chamber). two AQPs are present in mammalian cornea: AQP1 in endothelial cells and AQP5 in epithelial cells. AQP1 is involved in extrusion of fluid from the corneal stroma across the corneal endothelium and AQP5 in a similar process across the corneal epithelium. As a result both transparency and normal thickness (determined by hydration) of cornea depend upon AQP1 and AQP5. In AQP1-null mice the thickness of cornea is decreased, while in AQP5-null mice the thickness is increased202. In addition, AQP5 probably contributes to the generation of surface liquid that helps to protect cornea from mechanical injury171.

AQP3 found in conjunctiva (the epithelium that covers the outer margins of the eye) might help to lubricate the surface of the eye171. Recently, Candia and cowokers203 reported the presence of AQP5 in mammalian conjunctiva suggesting that AQP5 could be a potential target for pharmacological upregulation that may enhance fluid secretion in individuals with dry-eye syndromes.

AQP1 and AQP4 are present in the nonpigmented epithelium of the anterior ciliary body, a structure that contributes to the movement of AH; in addition, AQP1 is present in the trabecular meshwok and canals of Schlemm, structures that resorb AH out of the anterior chamber [Hamann et al., 1998, cited in171].

AQP1 is also present in the lens epithelium, whereas AQP0 constitutes 50% of the total membrane protein in the fibre cells of the lens. Recently, accelerated cataract formation was found in AQP1-null mice202. AQP0 was discovered in 1984 (MIP26) and only in 1995 it was identified as a WCPS [Mulders et al., 1995, cited in201]; although it has a low permeability to Water it contributes to the maintenance of lens transparency; mutations in AQP0 are associated with hereditary cataracts in humans [reviewed in171]; AQP0 also has a structural role as a cellcell ADHesion molecule204.

AQP4 is expressed in Müller cells in retina, colocalized with the K+ channel Kir4.1. Müller cells are supporting cells associated with bipolar cells, similarly to astrocytes in the CNS, associated with neurons [see refs. in201]. It was thought that AQP4 modulates Kir4.1 K+ channel function. However, recently Ruiz-Ederra and Verkman205 provided evidence against functional interaction between AQP4 and Kir4.1K+channel in retinal Müller cells.

There are two WCPSs in adipose tissue: AQP1 and AQP7. Although AQP1 is abundant in adipocytes its functional significance is not yet precisely known. Many studies have been performed on AQP7, reviewed in51, 206. Adipocytes hydrolyze or synthesize triglycerides (TG) in response to the whole body energy balance. The rapid increase in glycerol production during lipolysis results in rapid increase in intracellular osmotic pressure, which could damage the cell206; hence, a possible function of AQP7 as a glycerol channel in adipocytes appears of great importance. However, there is uncertainty as to the precise cellular localization of AQP7 in adipose tissue. Most researchers assume that AQP7 is localized in the adipocyte membrane51, while Skowronski et al.207 reported that it is actually expressed in the capillary endothelia of adipose tissue (and cardiac and striated muscle). More studies are necessary to solve this controversy and clearify how does glycerol exit the adipocyte and what is the function of AQP7 in the vessels51.

It seems that obesity is associated with a dysregulation of AQP7. Several AQP7-KO model mice were generated by different gene targeting strategies and, interestingly, show different phenotypes. The main difference between the different KOs is in their susceptibility to developing obesity [discussed in51]. The recent discovery of AQP7 in the pancreatic β-cells generated a novel hypothesis that the primary reason for the metabolic disturbance of the AQP7-KO mice may be the malfunctioning of β-cells rather than adipocytes208. A potential role of AQP7 in human obesity and, eventually through body weight changes in the development of type II diabetes is suggested by reports of decreased AQP7 expression in obese subjects209. More studies are necessary to clarify the role of AQP7 from adipose tissue and/or pancreatic β-cells in the development of obesity and the various metabolic disturbances observed in AQP7-KO mice.

In the skin AQP1 has been detected in the rat dermal capillaries [Agre et al., 2003 cited in210] and human neonatal dermis; [Marchini et al., 2003, cited in190]. AQP1 and AQP3 have also been found in epidermis and dermis in erythema toxicum neonatorum [Marchini et al., 2003, cited in210]. Special attention has been paid to the roles of AQP3 in the epidermis, where it is present in the plasma membrane of the basal cells and the adjacent intermediate cells170 and completely disappears in the outermost epidermal layer, the keratinized layer, also called stratum corneum (SC). AQP3 is also present in the associated structures of the epidermis such as hair follicles and sebaceous glands (including the Meibomian gland of the eyelid)170. SC is composed of keratinocytes embedded in a complex mixture of nonpolar lipids and serves as a barrier against the evaporation of Water from the skin. Matsuzaki et al. [cited in170] proposed that AQP3 in epidermal cells serves as machinery to supply Water to the Water-deprived epidermal cells from the underlying dermis where capillaires provide enough Water from the blood, followed by transfer of Water among cells (including highly differentiated cells in the upper layer of the epidermis) via gap junction intercellular channels. The crucial role of AQP3 in the hydration of the epidermis is supported by findings in AQP3-null mice: impaired skin hydration, elasticity and barrier function [reviewed in210].

Cao et al.211 found that ultraviolet (UV) radiation induces downregulation of AQP3 in keratinocytes, which result in reduced Water permeability, decreased cell migration and delayed wound healing; these effects are efficiently counteracted by all-trans retinoic acid. UV radiation decrease the Water content and Water-holding capacity of SC; the deprived Water content caused by UV radiation further damages the function of SC, leading to deleterious effects such as wrinkle formation and delayed wound healing [Weiss et al., 1988, cited in211].

On the other hand Hara-Chikuma and Verkman210 considered that glycerol rather than Water transporting function of AQP3 is important in skin physiology. The dry, relatively inelastic skin in AQP3-null mice was correlated with the humectant properties of glycerol and the impaired SC repair to impaired glycerol biosynthetic function. The authors suggested that the key role of AQP3 in epidermal physiology might be exploited in the development of improved cosmetics and therapies for skin diseases associated with altered skin Water content. In addition, it was found212 that AQP3-null mice were remarkably resistant to the development of skin tumors following exposure to a tumor initiator and phorbol ester promoter. The authors suggested that AQP3-facilitated transport in epidermal cell represents a novel mechanism of cell proliferation and tumorigenesis implicating cellular glycerol as a key determinant of cellular ATP energy. AQP3 may thus be an important determinant in skin tumorigenesis and hence a novel target for tumor prevention and therapy. This suggestion is also based on finding of greatly increased AQP3 expression in human skin squamous cell carcinoma212.

In the last decade many other studies regarding the possible implications of AQPs in cancer have been performed. The results are, however, conflicting. Some authors reported a decrease or loss of AQP1 in renal cell carcinoma, suggesting even a posible role of AQP1 as a prognostic or tumor grading marker; in contrast, other authors reported overexpression of AQP1 in lung and bronchoalveolar carcinoma [see citations in213]. In brain tumors (glioblastomas) AQP1 expression was found to increase with the grade of malignancy and the deletion of AQP1 in genetically modified mice reduces angiogenesis, a process essential for growth and spread of tumors194. In subsequent in vitro studies Hu and Verkman214 found that AQP1 expression in melanoma cell increased their migration and metastatic potential, suggesting a novel function for AQP expression in high-grade tumor and pointing to AQPs as posible targets in tumor therapy. Other authors reported heterogenous expression of AQP1 and other AQPs in a variety of tumors [see citations in215].

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