Polyphenols are bioactive molecules widely distributed in fruits, vegetables, cereals, and beverages. Polyphenols in food sources are extensively studied for their role in the maintenance of human health and in the protection against development of chronic/degenerative diseases. Polyphenols act mainly as antioxidant molecules, protecting cell constituents against oxidative damage. The enormous number of polyphenolic compounds leads to huge different mechanisms of action not fully understood. Recently, some evidence is emerging about the role of polyphenols, such as curcumin, pinocembrin, resveratrol, and quercetin, in modulating the activity of some aquaporin (AQP) isoforms. AQPs are integral, small hydrophobic water channel proteins, extensively expressed in many organs and tissues, whose major function is to facilitate the transport of water or glycerol over cell plasma membranes. Here we summarize AQP physiological functions and report emerging evidence on the implication of these proteins in a number of pathophysiological processes. In particular, this review offers an overview about the role of AQPs in brain, eye, skin diseases, and metabolic syndrome, focusing on the ability of polyphenols to modulate AQP expression. This original analysis can contribute to elucidating some peculiar effects exerted by polyphenols and can lead to the development of an innovative potential preventive/therapeutic strategy.
Aquaporins (AQPs) are integral, transmembrane, small hydrophobic water channel proteins. To date, the family consists of 13 members, highly conserved across the plant and animal kingdoms. The major AQP function is to facilitate the transport of water over cell plasma membranes; some members of AQP family are also able to transport other small molecules, such as glycerol, urea, CO2, ammonia, and nitric oxide (for a review see [
Each polyphenolic compound, or class of polyphenols, will be introduced and extensively described in the relevant section.
The first characterization of AQP, now named as AQP1, was performed in 1992 by Preston et al., who functionally described the protein from human red blood cells [
From a structural point of view, AQPs usually possess a tetrameric organization in membranes. Each monomer, functioning independently, is quite small, about 30 kDa, and comprises six transmembrane
Based on sequence homologies, AQPs could be divided in two groups, the mainly water-permeable AQPs (AQP1, AQP2, AQP4, AQP5, and AQP8) and the mainly glycerol-permeable aquaglyceroporins (AQP3, AQP7, AQP9, and AQP10) [
Besides water and glycerol, a variety of metabolically important small uncharged solutes were identified as AQP substrates [
Cells need to transfer water molecules from inside to outside the plasma membrane and vice versa in order to fulfill a multitude of essential processes, such as the delivery of nutrient substances to and the removal of waste molecules from tissues, the regulation of cell volume, the secretion of fluids from glands, and the migration and proliferation of cells; thus, the distribution of AQPs in different tissues and organs gives an indication on the many functions exerted by these channel proteins. AQPs are particularly abundant in cells appointed to transport fluids, for example, endothelia and epithelia of numerous organs, but unexpectedly also in some cell types not possessing an evident role in fluid transport, such as adipocytes or erythrocytes.
Kidney presents eight of the AQP members; five of them are involved in water absorption and in maintenance of body water homeostasis [
AQP isoforms are also expressed in blood cells. In macrophages and T lymphocytes, AQP3 facilitates hydrogen peroxide uptake, essential for cell migration toward chemokines [
Among several unexpected AQPs roles is their involvement in cell migration noticed in many cell types: in this process, AQPs promote transient local water transport [
The aquaglyceroporins AQP7 and AQP9 are expressed in the plasma membrane of adipocytes, where these proteins ensure the physiological plasma membrane glycerol permeability [
Many brain diseases, such as traumatic brain injury, stroke, brain tumors, and inflammation, result in cerebral edema, an excess of fluid accumulation due to a dysfunction of brain osmotic homeostasis. Water accumulation produces brain swelling [
Two classes of cerebral edema have been traditionally considered: cytotoxic, consisting in intracellular water accumulation established in the presence of intact blood-brain barrier, and vasogenic, characterized by blood-brain barrier disruption [
Involvement of AQP isoforms and polyphenols in some pathologies.
Pathology | AQP isoform involved | Active polyphenol | Action | Observed effects | References |
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Brain edema | AQP4 | Curcumin | Downregulation of AQP4 expression | Reduced neuroinflammation and neurological injury | [ |
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Traumatic brain injury | AQP4 | Curcumin | AQP4 inhibition | Reduced cerebral edema | [ |
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Spinal cord injury | AQP4 | Curcumin | Inhibition of AQP4 overexpression | Improvement of motor dysfunction and attenuation of spinal cord edema | [ |
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Spinal cord injury | AQP4 | Epigallocatechin gallate | Downregulation of AQP4 expression | Improvement of locomotor function and reduction of spinal cord edema | [ |
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Focal cerebral ischemia | AQP4 | Pinocembrin | Reduced AQP4 expression | Reduced neuronal apoptosis and astrocytic end-feet edema | [ |
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Brain injury | AQP1 | Curcumin | Reduced AQP1 expression | Reduction of intracranial pressure | [ |
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Lupus erythematosus | AQP4 | Curcumin | Increased AQP4 expression | Worsening of brain atrophy and increase of the edematous cell size | [ |
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Diabetic retinopathy | AQP4 | Quercetin and hesperetin | Downregulation of AQP4 expression | Neuroprotection, prevention of retinal edema, restoring of GSH normal levels, and improvement of antioxidant enzyme activities | [ |
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Skin disorders | AQP3 | Resveratrol | Reduced AQP3 expression | Inhibition of keratinocyte proliferation | [ |
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UV-produced skin damage | AQP3 | Chrysin | Inhibition of AQP3 downregulation | Protection of keratinocytes against apoptosis and ROS overproduction | [ |
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Obesity | AQP7 | Apple polyphenols | Increased AQP7 expression | Inhibition of adipocyte hypertrophy | [ |
Curcumin, a yellow phenolic pigment extracted from the rhizome of
In primary astrocyte cultures obtained from the cerebral cortices of mice, Laird and coworkers [
In a rat model of hypoxic-ischemic brain damage [
Also pinocembrin, one of the most abundant flavonoids in propolis, has been reported to protect the rat brain against ischemia injury. In a model of focal cerebral ischemia induced in rats by the middle cerebral artery occlusion, Gao and coworkers [
Spinal cord injury is the consequence of primary and secondary injury events. A physical injury to the spinal cord deriving from the laceration, contusion, and compression of the neural tissues represents the primary event. Secondary injury consists of inflammation processes and further damage following the primary injury [
Among the dietary polyphenolic compounds, epigallocatechin gallate, the most abundant green tea catechin, is known for its antioxidant action and free radical scavenging effect, but recent evidence has shown many additional actions for catechins and their metabolites [
Since spinal cord injury is associated with edema and changes in AQP4 expression, Ge and coworkers [
As previously reported, AQP4 is the principal water channel expressed in astrocytes throughout the central nervous system, but other members of the AQP family are present in the brain. In the apical surface of the choroid plexus, the main AQP isoform expressed is AQP1 [
Systemic lupus erythematosus represents a complex, autoimmune, and heterogeneous pathologic condition that includes edema, inflammation, and brain atrophy [
Since the knowledge about this human disease is very limited, a number of animal models have been developed. One of the widely used and accepted lupus erythematosus animal models is MRL/
AQPs are pores that facilitate water movement through cellular membranes, playing a crucial role in the eye physiology by maintaining water homeostasis [
Diabetic retinopathy is a serious complication of diabetes mellitus that can eventually lead to blindness. It is the result of microvascular retinal changes: during the first stage blood vessels swell and leaked fluid produces edema, as the disease progresses new vessels proliferate, impairing vision and ultimately detaching retina. The reasons of these changes are due to prolonged hyperglycemia, which leads to increased ROS generation in retina, establishing an oxidative stress condition associated with cellular inflammation and release of inflammatory cytokines, and to the hyperglycemia-induced formation of advanced glycation end products.
Since it has been shown that AQP4 is involved in the generation of diabetic retinal edema through a redistribution of its expression [
Quercetin is flavonol that can be found in many vegetables, and it is one of the major bioflavonoids in the human diet. Besides its well-known activity as antioxidant and phase 2 enzyme inducer [
In streptozotocin-induced diabetic rats, Kumar and coworkers [
Hesperetin is a flavanone glycoside contained in many fruits of
Therefore, the authors suggested that APQ4 inhibition could be a new therapeutic strategy for diabetic retinopathy and that polyphenols such as quercetin and/or hesperetin could be interesting candidates in such a new approach [
AQP3 is the most abundant aquaporin present in the skin, and it is expressed in the plasma membrane of epidermal keratinocytes [
Resveratrol is a stilbene polyphenol that is found in plants relevant to human diet such as grapes, blueberry, and raspberry. Resveratrol is one the most studied polyphenols, since it is involved in antiproliferative, antioxidant, anti-inflammatory, antiangiogenic, and antimetastatic effects in many different cell lines [
By using AQP3 siRNA, Wu and coworkers [
Ultraviolet light, both UVA and UVB, can penetrate the atmosphere and reach the skin. UV irradiation is able to produce a series of harmful effects on the human skin, spanning from sunburn to skin cancer [
Chrysin is a natural flavonoid, extracted from honey and propolis and also present in various edible plants [
The aquaglyceroporin AQP7 is expressed in the plasma membrane of adipocytes [
It has been reported that apple polyphenols exhibit antihyperglycemic, antihyperlipidemic, and anti-inflammatory properties [
This review presents an overview of experimental data reporting the strong implication of AQPs in several pathologies and diseases, and, for the first time to our knowledge, highlights the involvement of bioactive compounds, like polyphenols, in the prevention and/or reduction of such pathologies. In most cases, polyphenols act by the reduction of AQP levels or AQP overexpression due to disease; less frequently, these molecules reverse the downregulation of AQPs bringing levels to normal values.
The mechanism of action is still not clear, and certainly the beneficial effect cannot be ascribed only to antioxidant properties of polyphenols; therefore, further studies are required.
Nevertheless, AQP modulation represents an innovative potential therapeutic strategy. A challenge in AQP-based therapeutics is the identification of compounds acting as AQP inhibitors or being able to increase AQP expression. Polyphenols, largely occurring in plant-derived foods, could represent a healthy and intriguing opportunity in the prevention and treatment of diseases where AQPs are involved. Clinical trials on humans would be useful to corroborate the hypothesis of a possible AQP-based polyphenol treatment.
The authors report no conflict of interests.
Some data reported in this review have been obtained thanks to the financial support of “Fondazione del Monte di Bologna e Ravenna” (Italy).