الفهرس 
Aquaporins Discovery, Physiology and Clinical SignificanceOnly 14 pages are availabe for public view
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Abstract
Water transport in cells and tissues is essential for life. When water molecules move into or out of the cell or from one subcellular compartment to another they have to cross the cell membranes, which form the barrier between the interior and exterior of cell or between cell organelles and cytosol. The study of water transport began long before the molecular identification of water channels with studies of water-permeable tissues. 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.
The aquaporins (AQPs) are a family of small, hyDROPhobic, integral membrane proteins that act primarily as waterselective pores, facilitating osmotically driven water transport across cell plasma membranes. There are at least 13 mammalian AQPs (AQP0–AQP12), which have been divided into two groups on the basis of their permeability. AQPs 1, 2, 4, 5, and 8 function primarily as water-selective transporters; AQPs 3, 7, 9, and 10, termed ‘‘aquaglyceroporins’’, transport water as well as glycerol and possibly other small solutes. The AQPs are expressed in plasma membranes in a variety of cell types, where they function as pore-like passive transporters responding to transmembrane osmotic gradients (for water transport) or glycerol gradients (for glycerol transport). They consist of six transmembrane domains that enclose an aqueous pore.
AQP-facilitated water transport is involved in the urinary concentration mechanism, epithelial fluid secretion, brain edema, neural signal transduction, and cell migration. AQPs in epithelia facilitate transepithelial water transport in response to osmotic gradients, such as fluid absorption by kidney proximal tubule and fluid secretion in salivary gland. AQPs in microvascular endothelia and other cell types facilitate cell migration by enhancing water transport into lamellipodia at the leading edge of migrating cells. In contrast, the aquaglyceroporins are involved in metabolic pathways, such as adipose AQP7 in obesity and AQP9 in glycerol metabolism.
Several AQPs have been reported to be expressed in various cell types in mammalian skin, providing indirect evidence for their involvement in some of the functions mentioned above. AQP3, the most studied and well-validated AQP in skin, was first reported in keratinocytes of rat epidermis after its cloning from rat kidney in 1994 by several laboratories. AQP3 expression in plasma membranes in the basal layer of keratinocytes was also detected in human and mouse skin. Expression of AQP9 was also reported in cultures of human differentiated keratinocytes and in the stratum granulosum layer of mouse epidermis and expression of AQP10 was reported in human keratinocyte cultures.
AQP1 expression was found in rat dermal capillaries and human neonatal dermis. AQP1 was also expressed in microvessels in tumors implanted in skin, where it is involved in tumor angiogenesis. AQP5 expression was found in sweat glands in humans, rat, and mice. However, whether AQP5 is important in sweat secretion in humans is not known, as there are notable differences in sweat gland physiology between rodents and humans.AQP7 expression was found in the adipocytes in subcutaneous tissue. AQP7- knockout mice manifest progressive adipocyte hypertrophy as a consequence of reduced AQP7-facilitated plasma membrane glycerol exit in adipocytes. AQP7 is thus likely involved in hypertrophy of adipocytes in hypodermis.
AQP3 is the most abundant skin aquaglyceroporin. Both water and glycerol transport by AQP3 appears to play an important role in hydration of mammalian skin epidermis. In addition, it was suggested that glycerol transport by AQP3 is involved in the metabolism of lipids in skin as well as in the regulation of proliferation and differentiation of keratinocytes. Finally, AQP3 is also believed to be important in wound healing, as a water channel by facilitating cell migration, and as a glycerol transporter by enhancing keratinocyte proliferation and differentiation.
Altered AQP3 expression has been found in a variety of skin diseases. AQP3 expression in Langerhans cell, dendritic cells, macrophages, neutrophils, and eosinophils in erythema toxicum neonatorum, as well as in epidermal keratinocytes, suggesting involvement of AQP3 in the skin immune system at birth. Increased AQP3 transcript and protein expression was found in atopic eczema,suggesting that increased AQP3 contributed to water loss and dry skin. AQP3 expression was absent in epidermal spongiosis associated with eczema, with suggesting a possible relationship between absence of AQP3 and intercellular edema. AQP3 is expressed strongly in skin squamous cell carcinomas, suggesting involvement of AQP3-facilitated glycerol transport in cell proliferation during tumorigenesis.Whether altered AQP3 expression is involved in a significant way in the pathophysiology of skin diseases remains to be established. Changes in AQP3 expression may represent only secondary responses to various disease processes.
Aquaporins are important targets for drugs that could be used to study aquaporin function. Knockout phenotypes of kidney aquaporins suggest that aquaporin blockers could function as diuretics and blockers of brain AQP4, could reduce fatal brain swelling (edema) after stroke or head trauma. AQP7 specific inhibitors could help to elucidate its function in glycerol transport and contribute to developing novel treatments of type II diabetes and obesity. AQP3 modulation by topical drugs may be of benefit in a variety of common skin disorders associated with epidermal hyperproliferation, such as skin carcinogenesis, psoriasis and atopic dermatitis, and repair of burn and other wounds. The real therapeutic potential of AQPs as drug targets will depend upon successful development of such novel methodologies to identify high-affinity and highly selective modulators that target a particular subtype of AQP of choice from the available large collections of combinatorial small molecules and natural compounds, and the evaluation of their in vivo efficacy.
In our opinion we think that the discovery of aquaporins opens a new field of research and is certainly an area worth watching. It will unlock a lot of secrets of many diseases and give new hope for treatment.